Tropomyosin receptor kinase (trk) degradation compounds and methods of use

ABSTRACT

This disclosure relates to bivalent compounds (e.g., bi-functional small molecule compounds), compositions comprising one or more of the bivalent compounds, and to methods of use the bivalent compounds for the treatment of certain disease in a subject in need thereof. The disclosure also relates to methods for identifying such bivalent compounds.

CROSS REFERENCE

This application is a continuation of U.S. application Ser. No.17/269,670, filed Feb. 19, 2021, which is a § 371 U.S. National StageEntry of International Application No. PCT/CN2019/101850, filed Aug. 21,2019, and claims the benefit of International Application No.PCT/CN2019/086894, filed May 14, 2019, and International Application No.PCT/CN2018/101715, filed Aug. 22, 2018, each of which is herebyincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

This disclosure relates to bivalent compounds (e.g., bi-functional smallmolecule compounds), compositions comprising one or more of the bivalentcompounds, and to methods of use of the bivalent compounds for thetreatment of certain diseases in a subject in need thereof. Thedisclosure also relates to methods for identifying such bivalentcompounds.

SUMMARY OF THE INVENTION

According to one aspect of the present disclosure, a bivalent compounddisclosed herein comprises a tropomyosin receptor kinase (TRK) ligandconjugated to a degradation tag, or a pharmaceutically acceptable saltor analog thereof.

In one embodiment, the TRK ligand is capable of binding to a TRK proteincomprising TRK, a TRK mutant, TRK deletion, or a TRK fusion protein.

In another embodiment, the TRK ligand is a TRK kinase inhibitor or aportion of TRK kinase inhibitor.

In another embodiment, the TRK ligand is selected from the groupconsisting of altiratinib (DCC2701, DCC-270, DP-5164), sitravatinib(MGCD516), cabozantinib (XL-184, BMS-907351), dovitinib (TKI-258,CHIR-258), entrectinib (RXDX-101), milciclib (PHA-848125AC), belizatinib(TSR-011), GZ389988, pegcantratinib, AZD7451, larotrectinib (LOXO-101;ARRY-470), TPX-0005, LOXO-195, regorafenib, DS-6051b, F17752, PLX7486,AZD-6918, ASP7962, ONO-4174, PF-06273340, GNF-8625, and analogs thereof.

In another embodiment, the degradation tag binds to an ubiquitin ligase,or is a hydrophobic group or a tag that leads to misfolding of the TRKprotein.

In another embodiment, the ubiquitin ligase is an E3 ligase.

In another embodiment, the E3 ligase is selected from the groupconsisting of a cereblon E3 ligase, a VHL E3 ligase, a MDM2 ligase, aTRIM24 ligase, a TRIM21 ligase, a KEAP1 ligase, and an IAP ligase.

In another embodiment, the degradation tag is selected from the groupconsisting of pomalidomide, thalidomide, lenalidomide, VHL-1,adamantane, 1((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane, nutlin-3a,RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, and analogsthereof.

In another embodiment, the TRK ligand is conjugated to the degradationtag via a linker moiety.

In another embodiment, the TRK ligand comprises a moiety of Formula 1

-   wherein-   X is selected from CR′R″, CO, O, S, SO, SO₂, and NR′, wherein

R′ and R″ are independently selected from hydrogen, halogen. OH,optionally substituted C₁-C₈ alkyl, optionally substituted C₁₋₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈ alkylamino, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl,optionally substituted C₃-C₁₀ cycloalkyl, optionally substitutedC₃-C₁₀cycloalkoxy, and optionally substituted 3-10 memberedheterocyclyl; or

R′ and R″ together with the atom to which they are connected form anoptionally substituted 3-8 membered cycloalkyl or heterocyclyl ring;

R is selected from optionally substituted C₁-C₈ alkyl, optionallysubstituted C₃-C₁₀ cycloalkyl, optionally substituted 3-10 memberedheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl;

R¹, R², and R³ are independently selected from hydrogen, halogen, CN,NO₂, OR⁵, SR⁶, NR⁷R⁸, COR⁵, CO₂R⁵, C(O)NR⁷R⁸, SOR⁵, SO₂R⁵, SO₂NR7R⁸,NR⁷C(O)R⁸, NR⁵C(O)NR⁷R₈, NR₇SOR⁸, NR₇SO₂R⁸, optionally substituted C₁-C₈alkyl, optionally substituted C₁-C₈ alkoxy, optionally substitutedC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl,optionally substituted C₃-C₁₀ cycloalkyl, optionally substituted C₃-C₁₀cycloalkoxy, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₂-C₈ alkenyl, and optionally substituted C₂-C₈alkenyl, wherein

R⁵, R⁶, R⁷, and R⁸ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl.optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substitutedC₃-C₁₀ cycloalkyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted aryl, or optionally substitutedheteroaryl, or

R⁷ and R⁸ together with the atom to which they are connected form anoptionally substituted 4-8 membered heterocyclyl ring;

R⁴ is connected to the linker moiety of the bivalent compound, and isselected from a bond, OR⁹, SR⁹, NR¹⁰R¹¹, COR⁹, CO₂R⁹, CONR¹⁰R¹¹, SOR⁹,SO₂R⁹, SO₂NR¹⁰R¹¹, NR¹⁰COR¹¹, NR⁹CONR¹⁰R¹¹, NR¹⁰SOR¹¹, NR¹⁰SO₂R¹¹,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₁-C₈cycloalkoxy, optionally substituted 3-8membered heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, aryl, and optionally substituted heteroaryl,wherein

R⁹, R¹⁰, and R¹¹ are independently selected from null, a bond, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkoxy, optionally substituted 3-8membered heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

R¹⁰ and R¹¹ together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring; and

Ar is selected from aryl and heteroaryl group, each of which isoptionally substituted with one or more substituents independentlyselected from hydrogen, halogen, CN, NO₂, OR¹², SR¹², NR¹³R¹⁴, COR¹²,CO₂R¹², CONR¹³R¹⁴, SOR¹², SO₂R¹², SO₂NR¹³R¹⁴, NR¹³COR¹⁴,NR¹⁵C(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, optionally substituted C₁-C₈alkyl, optionally substituted C₁-C₈alkoxy, optionally substitutedC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted C₃-C₈cycloalkoxy, optionally substituted 3-8 membered heterocyclyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted aryl, and optionally substitutedheteroaryl, wherein

R¹², R¹³, R¹⁴ and R¹⁵ are independently selected from hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkoxy, optionally substituted 3-8membered heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

R¹³ and R¹⁴ together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

In one embodiment, X is selected from CR′R″, O, and NR′; wherein

R′ and R″ are independently selected from hydrogen, F, OH, optionallysubstituted C1-C3 alkyl, and optionally substituted C1-C3 alkoxy; or

R′ and R″ together with the atom to which they are connected form anoptionally substituted 3-6 membered cycloalkyl or heterocyclyl ring.

In another embodiment, X is selected from CH₂, cyclopropylene, CHF, CF₂,O, NH, NCH₃, NCH₂CH₃, and N-isopropyl.

In another embodiment, R is selected from optionally substituted C₃-C₈cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl.

In another embodiment, R is selected from optionally substituted phenyland optionally substituted heteroaryl.

In another embodiment, X is CH₂; and R is 3,5-difluorophenyl.

In another embodiment, R¹, R² and R³ are independently selected fromhydrogen, F, Cl, and OH.

In another embodiment, R⁴-Ar is selected from a moiety of formulae A1,A2, A3, and A4:

-   wherein-   * indicates the connection to the linker moiety of the bivalent    compound; and-   R^(a) is selected from hydrogen, halogen, CN, NO₂, OR¹², SR¹²,    NR¹³R¹⁴, COR¹², CO₂R¹², CONR¹³R¹⁴, SOR¹², SO₂R¹², SO₂NR¹³R¹⁴,    NR¹³COR¹⁴, NR¹⁵C(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, optionally    substituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxy,    optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted    C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted C₃-C₈ cycloalkoxy, optionally substituted 3-8    membered heterocyclyl, optionally substituted C₂-C₈ alkenyl,    optionally substituted C₂-C₈ alkenyl, optionally substituted aryl,    and optionally substituted heteroaryl, wherein

R¹², R¹³, R¹⁴, and R¹⁵ are independently selected from hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkoxy, optionally substituted 3-8membered heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, aryl, and optionally substituted heteroaryl,or

R¹³ and R¹⁴ together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, R⁴-Ar is selected from a moiety of formulae A1,A3, A3, and A4:

-   wherein-   * indicates the connection to the linker moiety of the bivalent    compound; and-   R^(a) is selected from hydrogen, halogen, NR¹³R¹⁴, and NR¹³COR¹⁴,    wherein

R¹³ and R¹⁴ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl,optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₃-C₈ cycloalkoxy,optionally substituted 3-8 membered heterocyclyl, optionally substitutedC₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, phenyl, andoptionally substituted C₅-C₆ heteroaryl, or

R¹³ and R¹⁴ together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, R^(a) is (tetrahydro-2H-pyran-4-yl)amino.

In another embodiment, the TRK ligand comprises a moiety of Formula 2:

-   wherein-   X¹, X², X³, and X⁴ are independently selected from C, CR′, and N    (preferly, X¹ is selected from CR′ and-   N, X², X³, and X⁴ are independently selected from C and N), wherein

R′ is selected from hydrogen, halogen, CN, NO₂, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl, and optionallysubstituted 3-6 membered heterocyclyl;

-   X is selected from null, a bond, C(R²)₂, C(R²)₂C(R²)₂, CO, C(R²)₂CO,    CONR², C(R²)₂O, C(R²)₂NR² and CH₂NR²;-   R¹ and R², at each occurrence, are independently selected from    hydrogen, halogen, OH, NH₂, CN, NO₂, optionally substituted C₁-C₄    alkyl, optionally substituted C₁-C₄ alkoxy, optionally substituted    C₁-C₄ alkylamino, optionally substituted C₁-C₄ alkoxyalkyl,    optionally substituted C₁-C₄ haloalkyl, optionally substituted C₁-C₄    hydroxyalkyl, optionally substituted C₁-C₄alkylaminoC₁-C₄alkyl,    optionally substituted C₃-C₆cycloalkyl, optionally substituted C₃-C₆    cycloalkoxy, and optionally substituted 3-6 membered heterocyclyl;-   n is 1 to 4;-   R³ is connected to the linker moiety of the bivalent compound either    directly or through R⁴;-   R³ and R⁴ are independently selected from null, a bond, OR⁵, SR⁵,    NR⁶R⁷, COR⁷, CO₂R⁵, CONR⁶R⁷, SOR⁵, SO₂R⁵, SO₂NR⁶R⁷, NR⁶COR⁷,    NR⁵C(O)NR⁶R⁷, NR⁶SOR⁷, NR⁶SO₂R⁷, optionally substituted C₁-C₈ alkyl,    optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted    C₁-C₈haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl,    optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally    substituted C₃-C₈ optionally substituted C₃-C₈cycloalkoxy,    optionally substituted 3-8 membered heterocyclyl, optionally    substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl,    optionally substituted aryl, and optionally substituted heteroaryl,    wherein

R⁵, R⁶ and R⁷ are independently selected from null, a bond, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₆cycloalkyl, optionally substituted 3-8 membered heterocyclyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R⁶ and R⁷ together with the atom to which they are connected form a 3-8membered cycloalkyl or 4-8 membered heterocyclyl ring; and

-   Ar¹ and Ar² are independently selected from aryl and heteroaryl,    each of which is optionally substituted with one or more    substituents independently selected from halogen, CN, NO₂, OR¹⁰,    SR¹⁰, NR¹¹R¹², COR¹⁰, CO₂R¹⁰, CONR¹¹R¹², SOR¹⁰, SO₂R¹⁰, SO₂NR¹¹R¹²,    NR¹¹COR¹², NR¹⁰C(O)NR¹¹R¹², NR¹¹SOR¹², NR¹¹SO₂R¹², optionally    substituted C₁-C₈ alkyl, optionally substituted    C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,    optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted    C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₇ cycloalkyl,    optionally substituted 3-7 membered heterocyclyl, optionally    substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl,    optionally substituted aryl, and optionally substituted heteroaryl,    wherein

R¹⁰, and R¹¹, and R¹² are independently selected from null, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, or

R¹¹ and R¹² together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

In one embodiment, X¹ is selected from CR′ and N, wherein R′ is selectedfrom hydrogen, F, Cl, CH₃, CF₃, and cyclopropyl.

In another embodiment, X², X³, and X⁴ are independently selected from Cand N.

In another embodiment, X is selected from a bond, CH₂, CH₂CH₂, CO,CH₂CO, CONH, CONCH₃, CH₂O, CH₂NH, and CH₂NCH₃.

In another embodiment, R¹ and R², at each occurrence, are independentlyselected from hydrogen, F, Cl, OH, optionally substituted C₁-C₄ alkyl,optionally substituted C₁-C₄alkoxy, optionally substituted C₁-C₄alkylamino, optionally substituted C₁-C₄ haloalkyl, optionallysubstituted C₃-C₆ cycloalkyl, optionally substituted C₃-C₆ cycloalkoxy,and optionally substituted 3-6 membered heterocyclyl.

In another embodiment, X is CH₂; and Ar¹ is 3-fluorophenyl.

In another embodiment, R³ is connected to the linker moiety of thebivalent compound directly, and R³ is selected from null, a bond, OR⁵,SR⁵, NR⁶R⁷, COR⁵, CO₂R⁵, CONR⁶R⁷, SOR⁵, SO₂R⁵, SO₂NR⁶R⁷, NR⁶COR⁷,NR⁵C(O)NR⁶R⁷, NR⁶SOR⁷, NR⁶SO₂R⁷, optionally substituted C₁-C₈ alkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionallysubstituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted 3-8 membered. heterocyclyl,optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted aryl, and optionally substitutedheteroaryl, wherein

R⁵, R⁶ and R⁷ are independently selected from null, a bond, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₆ cycloalkyl, optionally substituted 3-8 membered heterocyclyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R⁶ and R⁷ together with the atom to which they are connected for n a 4-8membered cycloalkyl or heterocyclyl ring.

In another embodiment, R³ is connected to the linker moiety of thebivalent compound through R⁴, and

-   R³ and R⁴ are independently selected from null, a bond, OR⁵, SR⁵,    NR⁶R⁷, COR⁵, CO₂R⁵, CONR⁶R⁷, SOR⁵, SO₂R⁵, SO₂NR⁶R⁷, NR⁶COR⁷,    NR⁵C(O)NR⁶R⁷, NR⁶SOR⁷, NR⁶SO₂R⁷, optionally substituted C₁-C₈ alkyl,    optionally substituted C₁-C₈alkoxyC₁-C₈ alkyl, optionally    substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈    hydroxyalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl,    optionally substituted C₃-C₈ cycloalkyl, optionally substituted 3-8    membered heterocyclyl, optionally substituted C₂-C₈ alkenyl,    optionally substituted C₂-C₈ alkynyl, optionally substituted aryl,    and optionally substituted heteroaryl, wherein

R⁵, R⁶ and R⁷ are independently selected from null, a bond, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₆ cycloalkyl, optionally substituted 3-8 membered heterocyclyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R⁶ and R⁷ together with the atom to which they are connected form a 4-8membered cycloalkyl or heterocyclyl ring.

In another embodiment,

-   Ar¹ is selected from C₆-₁₀ aryl and C₅-C₁₀ heteroaryl, each of which    is optionally substituted with one or more substituents    independently selected from F, Cl, CN, NO₂, OR¹⁰, NR¹¹R¹², COR¹⁰,    CO₂R¹⁰, CONR¹¹R¹², SOR¹⁰, SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹COR¹²,    NR¹⁰C(O)NR¹¹R¹², NR¹¹SOR¹², NR¹¹SO₂R¹², optionally substituted C₁-C₆    alkyl, optionally substituted C₁-C₆ alkoxyalkyl, optionally    substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆    hydroxyalkyl, optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl,    optionally substituted C₃-C₇ cycloalkyl, optionally substituted 3-7    membered heterocyclyl, optionally substituted C₂-C₆ alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted aryl,    and optionally substituted C₄-C₅ heteroaryl, wherein

R¹⁰, R¹¹, and R¹² are independently selected from null, hydrogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₇₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, or

R¹¹ and R¹² together with the atom to which_(—) they are connected forma 4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment,

-   Ar² is selected from C₆-C₁₀ aryl and C₅-C₁₀ heteroaryl, each of    which is optionally substituted with one or more substituents    independently selected from F, Cl, CN, NO₂, OR¹⁰, NR¹¹R¹², COR¹⁰,    CO₂R¹⁰, CONR¹¹R¹², SOR¹⁰, SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹COR¹²,    NR¹⁰C(O)NR¹¹R¹², NR¹¹SOR¹², NR¹¹SO₂R¹², optionally substituted C₁-C₆    alkyl, optionally substituted C₁-C₆ alkoxyalkyl, optionally    substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆    hydroxyalkyl, optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl,    optionally substituted C₃-C₇cycloalkyl, optionally substituted 3-7    membered heterocyclyl, optionally substituted C₂-C₆ alkenyl,    optionally substituted C₂-C₆ alkynyl, optionally substituted aryl,    and optionally substituted C₄-C₅ heteroaryl, wherein

R¹⁰, R¹¹, and R¹² are independently selected from null, hydrogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, or

R¹¹ and R¹² together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, R³-Ar² is selected from a moiety of formulae B1and B2:

-   wherein-   * indicates the connection to the linker moiety of the bivalent    compound;-   Y¹, Y², Y³, and Y⁴ are independently selected from CH and N, with    the proviso that up to 3 of Y¹, Y², Y³, and Y⁴ are N;-   each R^(a) is independently selected from hydrogen, halogen, CN,    NO₂, OR¹², SR¹², NR¹³R¹⁴, COR¹², CO₂R¹², CONR¹³R¹⁴, SOR¹², SO₂R¹²,    SO₂NR¹³R¹⁴, NR¹³COR¹⁴, NR¹⁵C(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴,    optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈    alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally    substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈    cycloalkyl, optionally substituted C₃-C₈ cycloalkoxy, optionally    substituted 3-8 membered heterocyclyl, optionally substituted C₂-C₈    alkenyl, optionally substituted C₂-C₈ alkynyl, optionally    substituted aryl, and optionally substituted heteroaryl, wherein

R¹², R¹³, R¹⁴, and R¹⁵ are independently selected from hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkoxy, optionally substituted 3-8membered heterocyclyl, optionally substituted C₂-C₈ alkenyl optionallysubstituted C₂-C₈ alkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

R¹³ and R¹⁴ together with the atom to which they are connected form a4-8membered cycloalkyl or heterocyclyl ring;

-   m is 0 to 4; and-   R³ is the same as defined in Formula 2.

In another embodiment, R³-Ar² is selected from a moiety of formula B3:

-   Wherein-   * indicates the connection to the linker moiety of the bivalent    compound;-   Y¹, Y², Y³, and Y⁴ are independently selected from CR^(a), N, O, and    S, with the proviso that up to 3 of Y¹, Y², Y³, and Y⁴ are N;-   each R^(a) is independently selected from hydrogen, halogen, CN,    NO₂, OR¹², SR¹², NR¹³R¹⁴, COR¹², CO₂R¹², CONR¹³R¹⁴, SOR¹², SO₂R¹²,    SO₂NR¹³R¹⁴, NR¹³COR¹⁴, NR¹⁵C(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴,    optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈    alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally    substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈    cycloalkyl, optionally substituted C₃-C₈ cycloalkoxy, optionally    substituted 3-8 membered heterocyclyl, optionally substituted C₂-C₈    alkenyl, optionally substituted C₂-C₈ alkynyl, optionally    substituted aryl, and optionally substituted heteroaryl, wherein

R¹², R¹³, R¹⁴, and R¹⁵ are independently selected from hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkoxy, optionally Substituted 3-8membered heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

R¹³ and R¹⁴ together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring;

-   m is 0 to 4; and-   R³ is the same as defined in Formula 2.

In another embodiment, X¹ is N; X² is N; X³ is C; X⁴ is C; X is CH₂; Ar¹is 3-fluorophenyl; and Ar² is 2-pyridyl.

In another embodiment, the TRK ligand comprises a moiety of FORMULA 3:

-   wherein-   X¹, X², X³, and X⁴ are independently selected from C, CR′, and N    (preferably, X¹ and X⁴ are independently selected from CR′ and N; X²    and X³ are independently selected from C and N), wherein

R′ is selected from hydrogen, halogen, CN, NO₂, and optionallysubstituted C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or 3-6 membered heterocyclyl;

-   X is selected from null, a bond, C(R²)₂, C(R²)₂C(R²)₂, CO, C(R²)₂CO,    NR²CO, OC(R²)₂, and NR²C(R²)₂;-   R¹ and each R² are independently selected from hydrogen, halogen,    OH, NH₂, CN, NO₂, optionally substituted C₁-C₄ alkyl, optionally    substituted C₁-C₄ alkoxy, optionally substituted C₁-C₄ alkylamino,    optionally substituted C₁-C₄ alkoxyalkyl, optionally substituted    C₁-C₄ haloalkyl, optionally substituted C₁-C₄ hydroxyalkyl,    optionally substituted C₁-C₄akylaminoC₁-C₄alkyl, optionally    substituted C₃-C₆ cycloalkyl, optionally substituted    C₃-C₆cycloalkoxy, and optionally substituted 3-6 membered    heterocyclyl;-   n is 1 to 4;-   R³ is selected from hydrogen, optionally substituted C₁-C₆ alkyl,    optionally substituted C₃-C₆ cycloalkyl, optionally substituted 3-6    membered heterocyclyl, optionally substituted C₁-C₆ alkoxyalkyl,    optionally substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆    hydroxyalkyl, and optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl;-   R⁴ is connected to the linker moiety of the bivalent compound either    directly or through R⁵, wherein R⁴ and R⁵ are independently selected    from null, OR⁶, SR⁶, NR⁷R⁸, COR⁶, CO₂R⁶, CONR⁷R⁸, SOR⁶, SO₂R⁶,    SO₂NR⁷R⁸, NR⁷COR⁸, NR⁹C(O)NR⁷R⁸, NR⁷SOR⁸, NR⁷SO₂R⁸, optionally    substituted C₁-C₈ alkyl, optionally substituted    C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,    optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted    C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted 3-8 membered heterocyclyl, optionally    substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl,    optionally substituted aryl, and optionally substituted heteroaryl,    wherein

R⁶, R⁷, R⁸, and R⁹ are independently selected from null, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₆ cycloalkyl, optionally substituted 3-8 membered heterocyclyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R⁷ and R⁸ together with the atom to which they are connected form a 4-8membered cycloalkyl or heterocyclyl ring:

-   Ar is selected from aryl and heteroaryl, each of which is optionally    substituted with one or more substituents independently selected    from halogen, CN, NO₂, OR¹⁰, SR¹⁰, NR¹¹R¹², COR¹⁰, CO₂R¹⁰,    CONR¹¹R¹², SOR¹⁰, SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹COR¹², NR¹⁰C(O)NR¹¹R¹²,    NR¹¹SOR¹², NR¹¹SO₂R¹², optionally substituted C₁-C₈ alkyl,    optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted    C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl,    optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally    substituted C₃-C₇ cycloalkyl, optionally substituted 3-7 membered    heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionally    substituted C₂-C₈ alkynyl, optionally substituted aryl, and    optionally substituted heteroaryl, wherein

R¹⁰, R¹¹, and R¹² are independently selected from null, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, or

R¹¹ and R¹² together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl rings.

In one embodiment, X¹ and X⁴ is selected from CR′ and N, and R′ isselected from hydrogen, F, Cl, CH₃, CF₃, and cyclopropyl.

In another embodiment, X² and X³ are independently selected from C andN.

In another embodiment, X is selected from a bond, CH₂, CH₂CH₂, CO,CH₂CO, CONH, CONCH₃, CH₂O, CH₂NH, and CH₂NCH₃.

In another embodiment, R¹ and each R² are independently selected fromhydrogen, F, Cl, OH, optionally substituted C₁-C₄ alkyl, optionallysubstituted C₁-C₄ alkoxy, optionally substituted C₁-C₄ alkylamino,optionally substituted C₁-C₄ haloalkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted C₃-C₆ cycloalkoxy, and optionallysubstituted 3-6 membered heterocyclyl.

In another embodiment, R³ is selected from hydrogen, CH₃, CH₂CH₃,propyl, isopropyl, cyclopropyl, CH₂F, CHF₂, and CF₃.

In another embodiment,

-   R⁴ is connected to the linker moiety of the bivalent compound    directly, and-   R⁴ is selected from null, OR⁶, SR⁶, NR⁷R⁸, COR⁶, CO₂R⁶, CONR⁷R⁸,    SOR⁶, SO₂R⁶, SO₂NR⁷R⁸, NR⁷COR⁸, NR⁹C(O)NR⁷R⁸, NR⁷SOR⁸, NR⁷SO₂R⁸,    optionally substituted C₁-C₈ alkyl, optionally substituted    C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,    optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted    C₁-C₈alkylaminoC₁-C₈ alkyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted 3-8 membered heterocyclyl, optionally    substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl,    optionally substituted aryl, and optionally substituted heteroaryl,    wherein

R⁶, R⁷, R⁸, and R⁹ are independently selected from null, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₆ cycloalkyl, optionally substituted 3-8 membered heterocyclyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl , heteroarylalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

R⁷ and R⁸ together with the atom to which they are connected form a 4-8membered cycloalkyl or heterocyclyl ring.

In another embodiment,

-   R⁴ is connected to the linker moiety of the bivalent compound    through R⁵, and-   R⁴ and R⁵ are independently selected from null, OR⁶, SR⁶, NR⁷R⁸,    COR⁶, CO₂R⁶, CONR⁷R⁸, SOR⁶, SO₂R⁶, SO₂NR⁷R⁸, NR⁷COR⁸, NR⁹C(O)NR⁷R⁸,    NR7SOR⁸, NR⁷SO₂R⁸, optionally substituted C₁-C₈ alkyl, optionally    substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈    haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally    substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈    cycloalkyl, optionally substituted 3-8 membered heterocyclyl,    optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈    alkynyl, optionally substituted aryl, and optionally substituted    heteroaryl, wherein

R⁶, R⁷, R⁸, and R⁹ are independently selected from null, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₆ cycloalkyl, optionally substituted 3-8 membered heterocyclyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R⁷ and R⁸ together with the atom to which they are connected form a 4-8membered cycloalkyl or heterocyclyl ring.

In another embodiment,

-   Ar is selected from aryl and heteroaryl, each of which is optionally    substituted with one or more substituents independently selected    from F, Cl, CN, NO₂, OR¹⁰, NR¹¹R¹², COR¹⁰, CO₂R¹⁰, CONR¹¹R¹², SOR¹⁰,    SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹COR¹², NR¹⁰C(O)NR¹¹R¹², NR¹¹SOR¹²,    NR¹¹SO₂R¹², optionally substituted C₁-C₆ alkyl, optionally    substituted C₁-C₆alkoxyalkyl, optionally substituted C₁-C₆haloalkyl,    optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted    C₁-C₆alkylaminoC₁-C₆alkyl, optionally substituted C₃-C₇ cycloalkyl,    optionally substituted 3-7 membered heterocyclyl, optionally    substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,    optionally substituted aryl, and optionally substituted C₄-C₅    heteroaryl, wherein

R¹⁰, R¹¹, and R¹² are independently selected from null, hydrogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, or

R¹¹ and R¹² together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, the TRK ligand is derived from any of thefollowing:

In another embodiment, the TRK ligand is derived from the following TRKkinase inhibitors: DS-6051b, F₁₇₇₅2, PLX⁷⁴⁸6, ALD-6918, ASP7962, VM902A,PF-₀₆₂73340, and ONO-₄₄₇4.

In another embodiment, the TRK ligand is selected from the gratinconsisting of:

In some embodiments, the degradation tag is a moiety selected from thegroup consisting of FORMULAE 5A, 5B, 5C, and 5D:

-   wherein

V, W, and X are independently selected from CR² and N;

Y is selected from CO, CR³R⁴, and N═N;

Z is selected from null, CO, CR⁵R⁶, NR⁵, O, optionally substitutedC₁-C₁₀ alkylene, optionally substituted C₁-C₁₀ alkenylene, optionallysubstituted C₁-C₁₀ alkynylene, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substitutedC₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl; preferly, Z is selected from null, CH₂, CH═CH,C≡C, NH and O;

R¹, and R² are independently selected from hydrogen, halogen, cyano,nitro, optionally substituted C₁-C₆ alkyl, optionally substituted 3 to 6membered carbocyclyl, and optionally substituted 4 to 6 memberedheterocyclyl;

R³, and R⁴ are independently selected from hydrogen, halogen, cyano,nitro, optionally substituted C₁-C₆ alkyl, optionally substituted 3 to 6membered carbocyclyl, and optionally substituted 4 to 6 memberedheterocyclyl; or R³ and R⁴ together with the atom to which they areconnected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl;and

R⁵ and R⁶ are independently selected from null, hydrogen, halogen, oxo,hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₆ alkyl,optionally substituted 3 to 6 membered carbocyclyl, and optionallysubstituted 4 to 6 membered heterocyclyl; or R⁵ and R⁶ together with theatom to which they are connected form a 3-6 membered carbocyclyl, or 4-6membered heterocyclyl.

In some embodiments, the degradation tag is a moiety selected from thegroup consisting of FORMULAE 5A, 5B, 5C, and 5D:

-   wherein

V, W, and X are independently selected from CR² and N;

Y is selected from CO and CH₂;

Z is selected from CH₂, H and O;

R¹ is selected from hydrogen, C₁-C₅ alkyl and halogen; and

R² is selected from hydrogen, halogen, and C₁-C₅ alkyl.

In some embodiments, the degradation tag is a moiety selected from thegroup consisting of FORMULAE 5E, 5F, 5G, 5H, and 5I:

-   wherein

U, V, W, and X are independently selected from CR² and N;

Y is selected from CR³R⁴, NR³ and O preferly, Y is selected from CH₂,NH, NCH₃ and O;

Z is selected from null, CO, CR⁵R⁶, NR⁵, O, optionally substitutedC₁-C₁₀ alkylene, optionally substituted C₁-C₁₀ alkenylene, optionallysubstituted C₁-C₁₀ alkynylene, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substitutedC₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl; preferly, Z is selected from null, CH₂, CH═CH,C≡C, NH and O;

R¹, and R² are independently selected from hydrogen, halogen, cyano,nitro, optionally substituted C₁-C₆ alkyl, optionally substituted 3 to 6membered carbocyclyl, and optionally substituted 4 to 6 memberedheterocyclyl;

R³, and R⁴ are independently selected from hydrogen, halogen, cyano,nitro, optionally substituted C₁-C₆ alkyl, optionally substituted 3 to 6membered carbocyclyl, and optionally substituted 4 to 6 memberedheterocyclyl; or R³ and R¹ together with the atom to which they areconnected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl;and

R⁵ and R⁶ are independently selected from null, hydrogen, halogen, oxo,hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₆ alkyl,optionally substituted 3 to 6 membered carbocyclyl, and optionallysubstituted 4 to 6 membered heterocyclyl; or R⁵ and R⁶ together with theatom to which they are connected form a 3-6 membered carbocyclyl, or 4-6membered heterocyclyl.

In one embodiment, the degradation tag is a moiety of FORMULA 6A:

-   wherein

R¹ and R² are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl,optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈ aminoalkyl, optionallysubstituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₇cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionallysubstituted C₂-C₈ alkenyl, and optionally substituted C₂-C₈ alkenyl; and

R³ is hydrogen, optionally substituted C(O)C₁-C₈ alkyl, optionallysubstituted C(O)C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C(O)C₁-C₈haloalkyl, optionally substituted C(O)C₁-C₈ hydroxyalkyl, optionallysubstituted C(O)C₁-C₈ aminoalkyl, optionally substitutedC(O)C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C(O)C₃-C₇cycloalkyl, optionally substituted C(O)(3-7 membered heterocyclyl),optionally substituted C(O)C₂-C₈ alkenyl, optionally substitutedC(O)C₂-C₈ alkynyl, optionally substituted C(O)OC₁-C₈alkoxyC₁-C₈alkyl,optionally substituted C(O)OC₁-C₈ haloalkyl, optionally substitutedC(O)OC₁-C₈ hydroxyalkyl, optionally substituted C(O)OC₁-C₈ aminoalkyl,optionally substituted C(O)OC₁-C₈alkylaminoC₁-C₈alkyl, optionallysubstituted C(O)OC₃-C₇ cycloalkyl, optionally substituted C(O)O(3-7membered heterocyclyl), optionally substituted C(O)OC₂-C₈ alkenyl,optionally substituted C(O)OC₂-C₈ alkenyl, optionally substitutedC(O)NC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C(O)NC₁-C₈ haloalkyl,optionally substituted C(O)NC₁-C₈ hydroxyalkyl, optionally substitutedC(O)NC₁-C₈ aminoalkyl, optionally substitutedC(O)NC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C(O)NC₃-C₇cycloalkyl, optionally substituted C(O)N(3-7 membered heterocyclyl),optionally substituted C(O)NC₂-C₈ alkenyl, optionally substitutedC(O)NC₂-C₈ alkynyl, optionally substituted P(O)(OH)₂, optionallysubstituted P(O)(OC₁-C₈alkyl)₂, and optionally substituted P(O)(OC₁-C₈aryl)₂.

In one embodiment, the degradation tag is a moiety selected from thegroup consisting of FORMULAE 6B, 6C, 6D, 6E and 6F:

-   wherein

R¹ and R² are independently selected from hydrogen, halogen, OH, NH₂,CN, optionally substituted C₁-C₈ alkyl, optionally substitutedC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ hydroxyalkyl, optionally substitutedC₁-C₈aminoalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl,optionally substituted C₃-C₇ cycloalkyl, optionally substituted 3-7membered heterocyclyl, optionally substituted C₂-C₈ alkenyl, andoptionally substituted C₂-C₈alkynyl; (preferably, R¹ is selected fromiso-propyl or tert-butyl; and R² is selected from hydrogen or methyl);.

R³ is hydrogen, optionally substituted C(O)C₁-C₈ alkyl, optionallysubstituted C(O)C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C(O)C₁-C₈haloalkyl, optionally substituted C(O)C₁-C₈ hydroxyalkyl, optionallysubstituted C(O)C₁-C₈ aminoalkyl, optionally substitutedC(O)C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C(O)C₃-C₇cycloalkyl, optionally substituted C(O)(3-7 membered heterocyclyl),optionally substituted C(O)C₂-C₈ alkenyl, optionally substitutedC(O)C₂-C₈ alkynyl, optionally substituted C(O)OC₁-C₈alkoxyC₁-C₈alkyl,optionally substituted C(O)OC₁-C₈ haloalkyl, optionally substitutedC(O)OC₁-C₈ hydroxyalkyl, optionally, substituted C(O)OC₁-C₈ aminoalkyl,optionally substituted C(O)OC₁-C₈alkylaminoC₁-C₈alkyl, optionallysubstituted C(O)OC₃-C₇ cycloalkyl, optionally substituted C(O)O(3-7membered heterocyclyl), optionally substituted C(O)OC₂-C₈ alkenyl,optionally substituted C(O)OC₂-C₈ alkynyl, optionally substitutedC(O)NC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C(O)NC₁-C₈ haloalkyl,optionally substituted C(O)NC₁-C₈ hydroxyalkyl, optionally substitutedC(O)NC₁-C₈ aminoalkyl, optionally substitutedC(O)NC₁-C₈alkylaminoC₁-C₈alkyl, optionally substitutedC(O)NC₃-C₇cycloalkyl, optionally substituted C(O)N(3-7 memberedheterocyclyl), optionally substituted C(O)NC₂-C₈ alkenyl, optionallysubstituted C(O)NC₂-C₈ alkynyl, optionally substituted P(O)(OH)₂,optionally substituted P(O)(OC₁-C₈ alkyl)₂, and optionally substitutedP(O)(OC₁-C₈ aryl)₂; and

R⁴ and R⁵ are independently selected from hydrogen, COR⁶, CO₂R⁶,CONR⁶R⁷, SOR⁶, SO₂R⁶, SO₂NR⁶R⁷, optionally substituted C₁-C₈ alkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-8 memberedcycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, wherein

R⁶ and R⁷ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy, optionallysubstituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-8 memberedcycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R⁴ and R⁵; R6 and R7 together with the atom to which they are connectedform a 4-8 membered cycloalkyl or heterocyclyl ring;

Ar is selected from aryl and heteroaryl, each of which is optionallysubstituted with one or more substituents independently selected from F,Cl, CN, NO₂, OR⁸, NR⁸R⁹, COR⁸, CO₂R⁸, CONR⁸R⁹, SOR⁸, SO₂R⁸, SO₂NR⁹R¹⁰,NR⁹COR¹⁰, NR⁸C(O)NR⁹R¹⁰, NR9SO₂R¹⁰, NR⁹SO₂R¹⁰, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxyalkyl, optionallysubstituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆ hydroxyalkyl,optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆alkynyl, optionally substituted aryl, and optionally substituted C₄-C₅heteroaryl, wherein

R⁸, R⁹, and R¹⁰ are independently selected from, null, hydrogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₇cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, or

R⁸ and R⁹; R⁹ and R¹⁰ together with the atom to which they are connectedform a 4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, the degradation tag is a moiety of FORMULA 7A:

wherein

V, W, X, and Z are independently selected from CR⁴ and N.

R¹, R², R³, and R⁴ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl,optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₃-C₇ cycloalkyl, optionallysubstituted 3-7 membered heterocyclyl, optionally substituted C₂-C₈alkenyl, and optionally substituted C₂-C₈ alkynyl.

In another embodiment, the degradation tag is a moiety of FORMULA 7B:

wherein

R¹, R², and R³ are independently selected from hydrogen, halogene,optionally substituted C₁-C₈ alkyl, optionally substitutedC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₃-C₇cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionallysubstituted C₂-C₈ alkenyl, and optionally substituted C₂-C₈ alkynyl;

R⁴ and R⁵ are independently selected from hydrogen, COR⁶, CO₂R⁶,CONR⁶R⁷, SOR⁶, SO₂R⁶, SO₂NR⁶R⁷, optionally substituted C₁-C₈ alkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted aryl-C₁-C₈alkyl,optionally substituted 3-8 membered cycloalkyl, optionally substituted3-8 membered heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, wherein

R⁶ and R⁷ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl,optionally substituted C₁-C₈alkylaminoC₁-C₈ alkyl, optionallysubstituted 3-8 membered cycloalkyl, optionally substituted 3-8 memberedheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl, or

R⁶ and R⁷ together with the atom to which they are connected form a 4-8membered cycloalkyl or heterocyclyl ring.

In another embodiment, the degradation tag is derived from any of thefollowing:

In another embodiment, the degradation is selected from the groupconsisting of:

In some embodiments, the linker moiety is of FORMULA 9:

-   wherein

A, W and B, at each occurrence, are independently selected from null, orbivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)N(R¹)R″,R′C(S)N(R¹)R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R¹)R″, R′SR″,R′SO₂R″, R′SO₂R″, R′SO₂N(R¹)R″, R′N(R¹)R″, R′NR¹COR″, R′NR¹C(O)OR″,R′NR′CON(R²)R′, R′NR¹C(S)R″, R′NR¹S(O)R″, R′NR¹S(O)₂R″, andR′NR¹S(O)₂N(R²)R″, wherein

R′ and R″ are independently selected from null, optionally substitutedR^(r)-(C₁-C₈ alkyl), or a moiety comprising of optionally substitutedC₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈ alkynylene, optionallysubstituted C₁-C₈ hydroxyalkylene, optionally substitutedC₁-C₈alkoxyC₁-C₈alkylene, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈ haloalkylene,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fusedcycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionallysubstituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl,optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl;

R^(r) is selected from optionally substituted 3-10 membered.carbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substitutedC₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl;

R¹ and R² are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl,optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionallysubstituted C₁-C₈ hydroxyalkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R¹ and R², R′ and R¹, R′ and R², R″ and R¹, R″ and R²together with the atom to which they are connected form a 3-20 memberedcycloalkyl or 4-20 membered heterocyclyl ring; and

m is 0 to 15.

In one embodiment, the linker moiety is of FORMULA 9:

-   wherein

A, W, and B, at each occurrence, are independently selected from null,CO, CO₂, C(O)NR¹, C(S)NR¹, O, S, SO, SO₂, SO₂NR¹, NR¹, NR¹CO, NR¹CONR²,NR¹C(S), optionally substituted C₁-C₈ alkyl, optionally substitutedC₁-C₈ alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionallysubstituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₃-C₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, and optionallysubstituted C₃-C₁₃ spiro heterocyclyl, wherein

R¹ and R² are independently selected from hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl,optionally substituted C₃-C₆ cycloalkoxy, optionally substituted 3-6membered heterocyclyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted C₁-C₆ alkoxyalkyl, optionally substituted C₁-C₆ haloalkyl,optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆alkylamino, and optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl; and

m is 0 to 15.

In one embodiment, the linker moiety is of FORMULA 9A:

-   wherein

R¹, R², R³ and R⁴, at each occurrence, are independently selected fromhydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substitutedC₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈ alkoxyalkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionallysubstituted C₁-C₈ alkylamino, and optionally substituted C₁-C₈alkylaminoC₁-C₈ alkyl, optionally substituted 3-10 membered carbocyclyl,optionally substituted 3-8 membered cycloalkoxy, optionally substituted3-10 membered carbocyclylamino, optionally substituted 4-8 memberedmembered heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

R¹ and R², R³ and R⁴ together with the atom to which they are connectedform a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

A, W and B, at each occurrence, are independently selected from null, orbivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)N(R⁵)R″,R′C(S)N(R⁵)R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR⁵R″, R′SR″, R′SO₂R″,R′SO₂N(R⁵)R″, R′N(R⁵)R″, R′NR⁵COR″, R′NR⁵C(O)OR″, R′NR⁵CON(R⁶)R″,R′NR⁵C(S)R″, R′NR⁵S(O)R″, R′NR⁵S(O)₂R″, and R′NR⁵S(O)₂N(R⁶)R″, wherein

R′ and R″ are independently selected from null, optionally substitutedR^(r)-(C₁-C₈ alkyl), or a moiety comprising of optionally substitutedC₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted alkynyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈ alkynylene, optionallysubstituted C₁-C₈ hydroxyalkylene, optionally substitutedC₁-C₈alkoxyC₁-C₈alkylene, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈ haloalkylene,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fusedcycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionallysubstituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl,optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl;

R^(r) is selected from optionally substituted 3-10 membered carbocyclyl,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fusedheterocyclyl, optionally substituted C₃-C₁₃ bridged cycloalkyl,optionally substituted C₃-C₁₃ bridged heterocyclyl, optionallysubstituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiroheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl;

R⁵ and R⁶ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl,optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionallysubstituted C₁-C₈ hydroxyalkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R⁵ and R⁶, R′ and R⁵, and R⁶, R″ and R⁵, R″ and R⁶ togetherwith the atom to which they are connected form a 3-20 memberedcycloalkyl or 4-20 membered heterocyclyl ring;

m is 0 to 15;

n, at each occurrence, is 0 to 15; and

o is 0 to 15.

In one embodiment, the linker moiety is of FORMULA 9A,

-   wherein

R¹, R², R³, and R⁴, at each occurrence, are independently selected fromhydrogen, halogen, CN, OH, NH₂, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₆ cycloalkyl, optionally substituted C₃-C₆cycloalkoxy, optionally substituted 3-6 membered heterocyclyl,optionally substituted C₁-C₆ alkoxy, optionally substituted C₁-C₆alkoxyalkyl, optionally substituted C₁-C₆ haloalkyl, optionallysubstituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆ alkylamino,and optionally substituted C₁-C₆alkylaminoC₁-C₈alkyl;

A, W, and B, at each occurrence, are independently selected from null,CO, CO₂, C(O)NR⁵, C(S)NR⁵, O, S, SO, SO₂, SO₂NR⁵, NR⁵, NR⁵CO, NR⁵CONR⁶,NR⁵C(S), optionally substituted C₁-C₈ alkyl, optionally substitutedC₁-C₈ alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionallysubstituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₃-C₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, and optionallysubstituted C₃-C₁₃ spiro heterocyclyl, wherein

R⁵ and R⁶ are independently selected from hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl,optionally substituted C₃-C₆ cycloalkoxy, optionally substituted 3-6membered heterocyclyl, optionally substituted C₃-C₆ alkoxy, optionallysubstituted C₁-C₆ alkoxyalkyl, optionally substituted C₁-C₆ haloalkyl,optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆alkylamino, and optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl;

m is to 15;

each n is 0 to 15; and

o is 0 to 15.

In another embodiment, the linker moiety is of FORMULA 9B:

-   wherein

R¹ and R², at each occurrence, are independently selected from hydrogen,halogen, hydroxyl, amino, cyan° , nitro, and optionally substitutedC₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy, optionally substitutedC₁-C₈ alkoxy C₁-C₈ alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈alkylamino, C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy,optionally substituted 3-10 membered carbocyclylamino, optionallysubstituted 4-10 membered heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl, or

R¹ and R² together with the atom to which they are connected form a 3-20membered cycloalkyl or 4-20 membered heterocyclyl ring;

A and B, at each occurrence, are independently selected from null, orbivalent moiety selected from R′-R″, R′COR″, R′CO₂R″, R′C(O)NR³R″,R′C(S)NR³R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R³)R′, R′SR″, R′SOR,R′SO₂R″, R′SO₂N(R³)R″, R′N(R³)R″, R′NR³COR″, R′NR³C(O)OR″,R′NR³CON(R⁴)R′, R′NR³C(S)R″, R′NR³S(O)R″, R′NR³S(O)₂R″, andR′NR³S(O)₂N(R⁴)R″, wherein

R′ and R″ are independently selected from null, optionally substitutedR^(r)-(C₁-C₈ alkyl), or a moiety comprising of optionally substitutedC₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈ alkynylene, optionallysubstituted C₁-C₈ hydroxyalkylene, optionally substitutedC₁-C₈alkoxyC₁-C₈alkylene, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈haloalkylene,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fusedcycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionallysubstituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl,optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl;

R^(r) is selected from optionally substituted 3-1° membered carbocyclyl,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fusedheterocyclyl, optionally substituted C₃-C₁₃ bridged cycloalkyl,optionally substituted C₃-C₁₃ bridged heterocyclyl, optionallysubstituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiroheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl;

R³ and R⁴ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl,optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionallysubstituted C₁-C₈ hydroxyalkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R³ and R⁴, R′ and R³, R′ and R⁴, R″ and R³, R″ and R⁴together with the atom to which they are connected form a 3-20 memberedcycloalkyl or 4-20 membered heterocyclyl ring;

each m is 0 to 15; and

n is 0 to 15.

In another embodiment, the linker moiety is of FORMULA 9B,

-   wherein,

each R¹, and each R² are independently selected from hydrogen, halogen,CN, OH, NH₂, and optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₆ cycloalkyl, optionally substituted C₃-C₆ cycloalkoxy,optionally substituted 3-6 membered heterocyclyl, optionally substitutedC₁-C₆ alkoxy, optionally substituted C₁-C₆ alkoxyalkyl, optionallysubstituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆ hydroxyalkyl,optionally substituted C₁-C₆ alkylamino, or C₁-C₆alkylaminoC₁-C₆alkyl,

each A and each B are independently selected from null, CO, CO₂,C(O)NR³, C(S)NR³, O, S, SO, SO₂, SO₂NR³, NR³, NR³CO, NR³CONR⁴, NR³C(S),and optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionallysubstituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₃-C₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, or C₃-C₁₃ spiroheterocyclyl, wherein

R³ and R⁴ are independently selected from hydrogen, and optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl,optionally substituted C₃-C₆ cycloalkoxy, optionally substituted 3-6membered heterocyclyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted C₁-C₆ alkoxyalkyl, optionally substituted C₁-C₆ haloalkyl,optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆alkylamino, or C₁-C₆alkylaminoC₁-C₆alkyl;

each m is 0 to 15; and

n is 0 to 15.

In another embodiment, in FORMULA 9B, m is 1 to 15.

In another embodiment, in FORMULA 9B, n is 1.

In another embodiment, in FORMULA 9B R¹ and R² are independentlyselected from hydrogen, and optionally substituted C₁-C₈ alkyl.

In another embodiment, the linker moiety is of FORMULA 9C:

-   wherein

X is selected from O, NH, and NR⁷;

R¹, R², R³, R⁴, R⁵, and R⁶, at each occurrence, are independentlyselected from hydrogen, halogen, hydroxyl, amino, cyano, nitro,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl,optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈ alkylamino, optionallysubstituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl;

A and B are independently selected from null, or bivalent moietyselected from R′—R″, R′COR″, R′CO₂R″, R′C(O)N(R⁸)R″, R′C(S)N(R⁸)R″,R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R⁸)R″, R′SR″, R′SOR″, R′SO₂R″,R′SO₂N(R⁸)R″, R′N(R⁸)R″, R′NR⁸COR″, R′NR⁸C(O)OR″, R′NR⁸CON(R⁹)R″,R′NR⁸C(S)R″, R′NR⁸S(O)R″, R′NR⁸S(O)₂R″and R′NR⁸S(O)₂N(R⁹)R″, wherein

R′ and R″ are independently selected from null, optionally substitutedR^(r)-(C₁-C₈ alkyl), or a moiety comprising of optionally substitutedC₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈ alkynylene, optionallysubstituted C₁-C₈ hydroxyalkylene, optionally substitutedC₁-C₈alkoxyC₁-C₈alkylene, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈ haloalkylene,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fusedcycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionallysubstituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl,optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl;

R^(r) is selected from optionally substituted 3-10 membered carbocyclyl,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fusedheterocyclyl, optionally substituted C₃-C₁₃ bridged cycloalkyl,optionally substituted C₃-C₁₃ bridged heterocyclyl, optionallysubstituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiroheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl;

R⁷, R⁸ and R⁹ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl,optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionallysubstituted C₁-C₈ hydroxyalkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl,

R′ and R″, R⁸ and R⁹, R′ and R⁸, R′ and R⁹, R″ and R⁸, R″ and R⁹together with the atom to which they are connected form a 3-20 memberedcycloalkyl or 4-20 membered heterocyclyl ring;

m, at each occurrence, is 0 to 15;

n, at each occurrence, is 0 to 15;

o is 0 to 15; and

p is 0 to 15.

In another embodiment, the linker moiety is of FORMULA 9C,

-   Wherein,

X is selected from O, NH, and NR⁷;

R¹, R², R³, R⁴, R⁵, and R⁶, at each occurrence, are independentlyselected from hydrogen, halogen, CN, OH, NH₂, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl, optionallysubstituted C₃-C₆ cycloalkoxy, optionally substituted 3-6 memberedheterocyclyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted C₁-C₆ alkoxyalkyl, optionally substituted C₁-C₆ haloalkyl,optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆alkylamino, and optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl;

A and B, at each occurrence, are independently selected from null, CO,CO₂, C(O)NR⁷, C(S)NR⁷, O, S, SO, SO₂, SO₂NR⁷, NR⁷, NR⁷CO, NR⁷CONR⁸,NR⁷C(S), optionally substituted C₁-C₈ alkyl, optionally substitutedC₁-C₈ alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionallysubstituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₃-C₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, and optionallysubstituted C₃-C₁₃ spiro heterocyclyl, wherein

R⁷ and R⁸ are independently selected from hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl,optionally substituted C₃-C₆ cycloalkoxy, optionally substituted 3-6membered heterocyclyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted C₁-C₆ alkoxyalkyl, optionally substituted C₁-C₆ haloalkyl,optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆alkylamino, and optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl;

each m is 0 to 15;

each n is 0 to 15;

o is 0 to 15; and

p is 0 to 15.

In one embodiment, in FORMULA 9C, m and n is 1, and p is 1 to 15;

In one embodiment, in FORMULA 9C, X is selected from O and NH;

In one embodiment, in FORMULA 9C, R¹, R², R³, R⁴, R⁵, and R⁶, areindependently selected from hydrogen, optionally substituted C₁-C₆alkyl.

In another embodiment, the linker moiety comprises a ring selected fromthe group consisting of a 3 to 13 membered ring, a 3 to 13 memberedfused ring, a 3 to 13 membered bridged ring, and a 3 to13 membered spiroring.

In another embodiment, the linker moiety comprises a ring selected fromthe group consisting of Formula C1 , C2, C3, C4 and C5:

In one embodiment, A, B and W, at each occurrence, are independentlyselected from null, CO, NH, NH—CO, CO—NH, CH₂—NH—CO, CH₂—CO—NH,NH—CO—CH₂, CO—NH—CH₂, CH₂—NH—CH₂—CO—NH, CH₂—NH—CH₂—NH—CO,NH—CO—CH₂—NH—CH—₂, CO—NH—CH₂—NH—CH₂, CH₂—NH—CH₂, R_(r)—CO, R_(r)—NH,R_(r)—NH—CO, R_(r)—CO—NH, R_(r)—CH₂—NH—CO, R_(r)—CH₂—CO—NH,R_(r)—NH—CO—CH₂, R_(r)—CO—NH—CH₂, R_(r)—CH₂—NH—CH₂—CO—NH,R_(r)—CH₂—NH—CH₂—NH—CO, R_(r)—NH—CO—CH₂—NH—CH₂, CO—NH—CH₂—NH—CH₂,R_(r)—CH₂—NH—CH₂.

In one embodiment, R^(r) is of Formula C1, C2, C3, C4 or C5.

In one embodiment, R^(r) is selected from

In another embodiment, the length of the linker is 0 to 40 linear atoms.

In another embodiment, the length of the linker is 0 to 20 linear atoms.

In another embodiment, the length of the linker is 0 to 8 linear atoms.

In another embodiment, the linker is selected from —(CO)—(CH₂)₁₋₈—,—(CH₂)₁₋₉—, —(CH₂)₁₋₂—(CO)—NH—(CH₂)₂₋₉—,—(CH₂)₁₋₂—(CO)—NH—(CH₂)₁₋₃—(OCH₂CH₂)—(CH₂)₀₋₁—(CO)—(CH₂)₁₋₃—(OCH₂CH₂)₁₋₇,—(CO)—(CH₂)₀₋₃-(alkenylene)-(CH₂)₀₋₃—,—(CO)—(CH₂)₀₋₃-(alkynylene)-(CH₂)₀₋₃-, —(CO)—(CH₂)₀₋₃-(3-8 memberedcarbocyclyl)-(CH₂)₀₋₃—, —(CO)—(CH₂)₀₋₃-(3-8 memberedheterocarboxyclyl)-(CH₂)₀₋₃—, —(CH₂))₀₋₃-(alkenylene)-(CH₂)₀₋₃—,—(CH₂)₀₋₃-(alkynylene)-(CH₂)₀₋₃—, —(CH₂)₀₋₃-(3-8 memberedcarbocyclyl)-(CH₂)₀₋₃—, and —(CH₂)₀₋₃(3-8 memberedheterocarbocyclyl)-(CH₂)₀₋₃—;

R^(r)—(CO)—(CH₂)₁₋₈—, R^(r)—(CH₂)₁₋₉—, R^(r)—(CH₂)₁₋₂—(CO)—NH—(CH₂)₂₋₉—,R^(r)—(CH₂)₁₋₂—(CO)—NH—(CH₂)₁₋₃—(OCH₂CH₂)₁₋₇—,R_(r)—(CH₂)₀₋₁—(CO)—(CH₂)₁₋₃—(OCH₂CH₂)₁₋₇—,R^(r)—(CO)—(CH₂)₀₋₃-(alkenylene)-(CH₂)₀₋₃-,R^(r)—(CO)—(CH₂)₀₋₃-(alkynylene)-(CH₂)₀₋₃—, R^(r)—(CO)—(CH₂)₀₋₃-(3-8membered carbocyclyl)-(CH₂)₀₋₃—, R_(r)-—CO)—(CH₂)₀₋₃-(3-8 memberedheterocarbocyclyl)-(CH₂)₀₋₃—, R^(r)-(CH₂)₀₋₃-(alkenylene)-(CH₂)₀₋₃—,R^(r)—(CH₂)₀₋₃-(alkynylene)-(CH₂)₀₋₃—, R^(r)—(CH₂)₀₋₃-(3-8 memberedcarbocyclyl)-(CH₂)₀₋₃—, and R^(r)—(CH₂)₀₋₃-(3-8 memberedheterocarbocyclyl)-(CH₂)₀₋₃—.

In some embodiments, the bivalent compound is selected from the groupconsisting of CPD-00I to CPD-206, or a pharmaceutically acceptable saltor analog thereof.

In some embodiments, the bivalent compound is selected from the groupconsisting of CPD-009, CPD-010, CPD-013, CPD-014, CPD-015, CPD-021,CPD-022, CPD-023, CPD-024, CPD-025, CPD026, CPD-027, CPD-028, CPD-029,CPD-030, CPD-031, CPD-032, CPD-033, CPD-044, CPD-047, CPD-049, CPD-050,CPD-051, CPD-052, CPD-053, CPD-054, CPD-055, CPD-056, CPD-057, CPD-059,CPD-060, CPD-062, CPD-064, CPD-065, and a pharmaceutically acceptablesalt or analog thereof.

In some embodiments, the bivalent compound is selected from the groupconsisting of TR-104, TR-105, TR-106, TR-107, TR-108, TR-109, TR-113,TR-115, TR-116, TR-117, TR-118, TR-119, TR-120, TR-121, TR-122, TR-123,TR-124, TR-125, TR-127, TR-128, TR-129, TR-130, TR-131, TR-132, TR-134,TR-135, TR-137, TR-140, TR-141, TR-142, TR-143, TR-144, TR-145, TR-146,TR-147, TR-149, TR-151, TR-152, TR-153, TR-155, TR-156, TR-157, TR-158,TR-160, TR-161, TR-162, TR-163, TR-164, TR-165, TR-166, TR-167, TR-168,TR-169, TR-171, TR-172, TR-173, TR-176, TR-177, TR-181, TR-184, TR-186,TR-189, TR-190, TR-191, TR-194, TR-196, TR-198, and a pharmaceuticallyacceptable salt or analog thereof.

In some embodiments, the bivalent compound is selected from the groupconsisting of TR-106, TR-108, TR-109, TR-113, TR-115, TR-116, TR-117,TR-119, TR-121, TR-122, TR-123, TR-124, TR-125, TR-127, TR-128, TR-129,TR-130, TR-131, TR-132, TR-135, TR-137, TR-140, TR-141, TR-142, TR-143,TR-144, TR-145, TR-146, TR-149, TR-151, TR-152, TR-155, TR-156 TR-160,TR-161, TR-162, TR-165, TR-166, TR-167, TR-168, TR-169, TR-171, TR-172,TR-173, TR-176, TR-181, TR-186, TR-189, TR-190, TR-191 TR-194, TR-196,TR-198, and a pharmaceutically acceptable salt or analog thereof.

In some embodiments, the bivalent compound is selected from the groupconsisting of TR-123), TR-172, TR-173, TR-181, TR-185, TR-186, TR-191,TR-196, TR-198, and a pharmaceutically acceptable salt or analogthereof.

In some embodiments, the bivalent compound is2-(2,6-Dioxopiperidin-3-yl)-4-((7-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione(CPD-009).

In some embodiments, the bivalent compound is2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione(CPD-010).

In some embodiments, the bivalent compound is2-(2,6-Dioxopiperidin-3-yl)-4-((4-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4-oxobutyl)amino)isoindoline-1,3-dione(CPD-013).

In some embodiments, the bivalent compound is2-(2,6-Dioxopiperidin-3-yl)-4-((5-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione(CPD-014).

In some embodiments, the bivalent compound is2-(2,6-Dioxopiperidin-3-yl)-4-((5-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione(CPD-015).

In some embodiments, the bivalent compound is2-(2,6-Dioxopiperidin-3-yl)4-((15-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)isoindoline-1,3-dione(CPD-021).

In some embodiments, the bivalent compound is(2S,4R)-1-((S)-2-(11-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-11-oxoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthinzol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-022).

In some embodiments, the bivalent compound is2-(2,6-Dioxopiperidin-3-yl)-4-((2-(4-(-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione(CPD-023).

In some embodiments, the bivalent compound is2-(2,6-Dioxopiperidin-3-yl)-4-((8-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-8-oxooctyl)amino)isoindoline-1,3-dione(CPD-024).

In some embodiments, the bivalent compound is2-(2,6-Dioxopiperidin-3-yl)-4-((18-(4-(6-(6-((R)-2-3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-18-oxo-3,6,9,12.15-pentoxaoctadecyl)amino)isoindoline-1,3-dione(CPD-025).

In some embodiments, the bivalent compound is2-(2,6-Dioxopiperidin-3-yl)-4-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3oxopropyl)amino)isoindoline-1,3-dione (CPD-026).

In some embodiments, the bivalent compound is2-(2,6-Dioxopiperidin-3-yl)4-((2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)isoindoline-1,3-dione(CPD-027).

In some embodiments, the bivalent compound is2-(2,6-Dioxopiperidin-3-yl)4-((2-(2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione(CPD-028).

In some embodiments, the bivalent compound is(2S,4R)-1-((S)-2-(8-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-029).

In some embodiments, the bivalent compound isN-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)4-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-030).

In some embodiments, the bivalent compound isN-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin4-yl)amino)-3,6,9,12-tetmoxapentadecan-15-oyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran4-yl)amino)benzamide(CPD-031).

In some embodiments, the bivalent compound isN-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-032).

In some embodiments, the bivalent compound is(2S,4R)-1-((S)-2-(8-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-033).

In some embodiments, the bivalent compound is(2S,4R)-1-(S)-2-(6-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methlythiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-044).

In some embodiments, the bivalent compound is(2S,4R)-1-((S)-2-(7-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran4-yl)amino)phenyl)piperazin-1-yl)-7-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-047).

In some embodiments, the bivalent compound isN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin4-yl)amino)heptanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-049).

In some embodiments, the bivalent compound isN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioixoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-050).

In some embodiments, the bivalent compound isN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-051).

In some embodiments, the bivalent compound isN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-052).

In some embodiments, the bivalent compound isN-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioixoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-053).

In some embodiments, the bivalent compound isN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoetadecan-18-oyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-054).

In some embodiments, the bivalent compound isN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-055).

In some embodiments, the bivalent compound isN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin4-yl)amino)hexanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-056).

In some embodiments, the bivalent compound isN-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-057).

In some embodiments, the bivalent compound isN-(2-(2-((2-(2,6-dioxopiperidin-3-yl)1,3-dioxoisoindolin-4-yl)amino)ethoxyl)ethoxy)-ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]-pyridazin-3-yl)pyridin-2-yl)piperazin-yl)acetamide(CPD-059).

In some embodiments, the bivalent compound isN-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(CPD-060).

In some embodiments, the bivalent compound isN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-062).

In some embodiments, the bivalent compound isN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(14-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12-trioxa-3-azatetradecyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-064).

In some embodiments, the bivalent compound isN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12,15,18-pentaoxa-3-azaicosyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-065).

In some embodiments, the bivalent compound is2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-4)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione(TR-123).

In some embodiments, the bivalent compound is2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)isoindoline-1,3-dione(TR-172).

In some embodiments, the bivalent compound is2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)isoindoline-1,3-dione(TR-173),

In some embodiments, the bivalent compound is2-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)isoindoline-1,3-dione(TR-181).

In some embodiments, the bivalent compound is3-(6-(3-(4-(6-(6-((R)-2-(3-florophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-185).

In some embodiments, the bivalent compound is3-(5-(3(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-186).

In some embodiments, the bivalent compound is3-(5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-191).

In some embodiments, the bivalent compound is3-(6-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-196).

In some embodiments, the bivalent compound is2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione(TR-198).

According to one aspect of the present disclosure, a compositiondisclosed herein comprises the bivalent compound or a pharmaceuticallyacceptable salt or analog thereof.

According to one aspect of the present disclosure, a method of treatinga tropomyosin receptor kinase (TRK)-mediated disease disclosed hereincomprises administering to a subject with a TRK-mediated disease thebivalent compound or a pharmaceutically acceptable salt or analogthereof.

In one embodiment, the TRK-mediated disease results from TRK expression,mutation, or fusion.

In one embodiment, wherein the subject with the TRK-mediated disease hasan elevated TRK function relative to a healthy subject without theTRK-mediated disease.

In one embodiment, the bivalent compound is selected from the groupconsisting of CPD-001 to CPD-206, or analogs thereof.

In one embodiment, the bivalent compound is administered to the subjectorally, parenterally, intradermally, subcutaneously, topically, orrectally. In one embodiment, the method further comprises administeringto the subject an additional therapeutic regimen for treating cancer.

In one embodiment, the additional therapeutic regimen is selected fromthe group consisting of surgery, chemotherapy, radiation therapy,hormone therapy, and immunotherapy.

In one embodiment, the TRK-mediated disease is selected from the groupconsisting of non-small cell lung cancer, colorectal cancer, gastriccancer, liver cancer, invasive breast cancer, lung adenocarcinoma,uterine cancer, adrenal cancer, pancreatic cancer, ovarian cancer,esophageal cancer, urinary bladder cancer, endometrial cancer, prostatecancer low-grade glioma, glioblastoma, Sptizoid cancer, soft tissuesarcoma, papillary thyroid carcinoma, head and neck squamous cellcarcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma,secretory breast carcinoma, mammary analogue secretory carcinoma, acutemyeloid leukemia, ductal carcinoma, pulmonary neuroendocrine tumors,pheochromocytoma, and Wilms' tumor.

In one embodiments, the TRK-mediated disease or condition comprisescancer, inflammatory diseases, acute and chronic pain, pruritus,bone-related diseases, neurodegenerative diseases, infectious diseases,and other diseases, including but not limited to neuroblastoma, prostatecancer, pancreatic cancer, melanoma, head and neck cancer, gastriccarcinoma, lung carcinoma, liver cancer, uterine cancer, adrenal cancer,biliary tree cancer, intestinal cancer, colorectal cancer, ovariancancer, lung carcinoma, small cell lung cancer, non-small cell lungcancer, gastric carcinoma, breast cancer, esophageal cancer, urinarybladder cancer, endometrial cancer, brain cancer, low-tirade glioma,glioblastoma, medulloblastoma, secratory breast cancer, secretory breastcarcinoma, salivary gland cancer, papillary thyroid carcinoma, ductalcarcinoma, adult myeloid leukemia, acute myeloid leukemia, large cellneuroendocrine tumors, pulmonary neuroendocrine tumors, sarcomas,pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenitalmesoblastic nephroma, secretory breast carcinoma, malignant fibroushistiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma,neuro-fibrosarcoma, neoplasms of the central nervous systems,osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma,Spitzoid cancer, Wilms' tumor, lymphomas (e.g. including Hodgkin'slymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma,mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma,B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplasticlarge cell lymphoinal, inflammatory lung diseases (e.g. asthma),inflammatory bowel diseases, (e.g. ulcerative colitis, Crohn's disease),inflammatory skin diseases (e.g. atopic dermatitis, eczema andpsoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain,cancer pain, surgical pain, inflammatory pain, neuropathic pain,nociceptive pain, pain of osteoarthritis, chronic low back pain, lowback pain of osteoporosis, pain of bone fracture, pain of rheumatoidarthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia,pain of pancreatitis, pain of interstitial cystitis, pain ofendometriosis, pain of irritable bowel syndrome, migraine, pain ofpulpitis, interstitial cystitis pain, painful bladder syndrome, centralpain syndromes, postsurgical pain syndromes, bone and joint pain,repetitive motion pain, dental pain, myofascial pain, perioperativepain, dysmennorhea, myofascial pain, angina pain, headache, primaryhyperalgesia, secondary hyperalgesia, primary allodynia, secondaryallodynia, other pain caused by central sensitization, systemiccutaneous pruritus, localized cutaneous pruritus, senile cutaneouspruritus, gestational pruritus, pruritus ani, vulvar pruritus,metastatic bone disease, treatment-induce bone loss, osteoporosis,rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget'sdisease, periodontal disease, osteolytic disease, multiple sclerosis,Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia,anorexia, demyelination and dysmyelination. In certain embodiments, thedisease or condition is a relapsed disease.

In one embodiment, the TRK-mediated disease is a relapsed cancer.

In one embodiment, the TRK mediated disease is refractory to one or moreprevious treatments.

According to one aspect of the present disclosure, a method foridentifying a bivalent compound which mediates degradation or reductionof TRK is disclosed. The method comprises:

providing a heterobifunctional test compound comprising an TRK ligandconjugated to a degradation tag through a linker;

contacting the heterobifunctional test compound with a cell comprising aubiquitin ligase and TRK;

determining whether TRK level is decreased in the cell; and

identifying the heterobifunctional test compound as a bivalent compoundwhich mediates degradation or reduction of TRK.

In one embodiment, the cell is a cancer cell.

In one embodiment, the cancer cell is a TRK-mediated cancer cell.

Incorporation by Reference

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1A shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with Entrectinib or bivalent compoundsCPD-001-CPD-022.

FIG. 1B shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with Entrectinib or bivalent compoundsCPD-023-CPD-044.

FIG. 1C shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with Entrectinib or bivalent compoundsCPD-045-CPD-065.

FIG. 2 shows an immunoblot of TPM3-TRKA fusion protein expressed by KM12cells after treatment with Entrectinib or bivalent compounds CPD-027,CPD-053, and CPD-060 at various time points.

FIG. 3 shows immunoblots TPM3-TRKA fusion protein expressed by KM12cells in subcutaneous xenograft tumors after treatment with a dose rangeof CPD-027, CPD-053, and CPD-060.

FIG. 4A shows a graph of KM12 cell viability vs. concentration ofbivalent compounds CPD-010, CPD-053, and CPD-057.

FIG. 4B shows KM12 and H358 cell viability vs. concentration of bivalentcompound CPD-053.

FIG. 5A shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with GNF-8625, LOXO101 or bivalent compoundsTR-104-TR-129.

FIG. 5B shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a dose range of TR-115, TR-116, TR-119,TR-123, TR-124, TR-127 or TR-129.

FIG. 5C shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a dose range of TR-130, TR-131, TR-132,TR-140, TR-146, TR-150 or TR-168.

FIG. 6A shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a dose range of TR-171, TR-172, TR-173or TR-176.

FIG. 6B shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a dose range of TR-177, TR-181, TR-182or GNF-8625.

FIG. 6C shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a dose range of TR-186, TR-188, TR-189or TR-190.

FIG. 6D shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a dose range of TR-191, TR-194, TR-196,TR198 or GNF-8625.

FIG. 7 shows immunoblots of overexpressed TPM3-TRKA, AGBL4-TRKB andETV6-TRKC fusion protein in KM12 cells after treatment with a dose rangeof TR-123.

FIG. 8A shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a dose range of compound TR-123 orTR-123-neg.

FIG. 8B shows an immunoblot of wild type TRKA protein expressed by HELcells after treatment with a dose range of compound TR-123 orTR-123-neg.

FIG. 9A shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a single dose of TR-123 or combinationswith MG-132, Bortezomib or MLN4924.

FIG. 9B shows an immunoblot of wild type TRKA protein expressed by HELcells after treatment with a single dose of TR-123 or combinations withMG-132, Bortezomib, MLN4924 or Pomatidomide.

FIG. 10A shows an immunoblot of TPM3-TRKA fusion protein in subcutaneousKM12 xenograft tumors after treatment with a dose range of TR-123.

FIG. 10B shows an immunoblot of TPM3-TRKA fusion protein expressed insubcutaneous KM12 xenograft tumors after treatment with TR-171, TR-172,TR-173, TR-177 or TR-181.

FIG. 11 shows a graph of plasma concentration of TR-123 vs. time pointspost dosing.

FIG. 12A shows a graph of subcutaneous KM12 xenograft tumor volume vs.days after treatment with a dose range of CPD-060.

FIG. 12B shows a graph of body weight vs. days after treatment with aclose range of CPD-060.

FIG. 13A shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a dose range of TR-202, TR-203 orTR-204.

FIG. 13B shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a dose range of TR-208, TR-210, TR-211or TR-214.

FIG. 13C shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a dose range of TR-215, TR216, TR-217,TR218, TR-219 or TR-220.

FIG. 13D shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a dose range of TR-221, TR-222, TR-223,TR-224, TR-225, TR-226 or TR-227.

FIG. 13E shows an immunoblot of TPM3-TRKA fusion protein expressed byKM12 cells after treatment with a dose range of TR-231, TR-232, TR-233,TR-234 or TR-235.

FIG. 14 shows a graph of plasma concentration of TR-198 over time afterdosing via intravenous injection or oral gavage.

FIG. 15A shows a graph of subcutaneous KM12 xenograft tumor volume as afunction of days after treatment with a dose range of TR-181 or a singledose of TR-198.

FIG. 15B shows a graph of body weight as a functional of days aftertreatment with a dose range of TR-181 or a single dose of TR-198.

FIG. 16A shows a graph of the percentage of weight born on the injuredlimb following treatment with a single dose of vehicle (Veh), TR-181 oribuprofen (Ibu) in rats.

FIG. 16B shows a graph of the percentage of weight born on the injuredlimb following treatment with a single dose of TR-181 or ibuprofen (Ibu)in guinea pigs.

DETAILED DESCRIPTION OF THE INVENTION

It is recognized in the present disclosure that tropomyosin receptorkinase (TRK) receptor family comprises three members, TRKA, TRKB andTRKC that are encoded by the NTRK1, NTRK2 and NTRK3 genes, respectively(Khotskaya et al., 2017). TRKs are receptor tyrosine kinases primarilyimplicated in development and functions of the neuronal tissues. Themain ligands of TRKs include nerve growth factor (NGF) for TRKA,brain-derived growth factor (BDGF) for TRKB, and neurotrophins for TRKC(Vaishnavi et al., 2015). The binding of ligands to the extracellulardomains of TRKs induces dimerization and activation of the receptors,which activates downstream signal transduction pathways, such asPI3K/AKT, RAF/MEK/ERK, and PLCγ pathways. These pathways have wellestablished roles to support cellular proliferation, survival, andpromote oncogenesis (Hanahan and Weinberg, 2011).

It is further recognized herein that, like many other oncogenic receptortyrosine kinases, TRKs are aberrantly activated in a variety of humanmalignancies. Interestingly, the primary molecular mechanism activatingTRKs in cancer is not point mutations but in-frame fusions of NTRK genes(Vaishnavi et al., 2015). Typically, the 3′ regions of the NTRK genesare joined with the 5′ regions of a partner gene due to chromosomalrearrangement. The resulted chimeric proteins always retain the kinasedomain of TRK proteins, indicating that the catalytic functions arecrucial to the transforming activities. Loss of the 5′ regions of theNTRK genes that encode the self-inhibitory domains renders these fusionkinases constitutively active. Additionally, expression of the chimericproteins is driven by the promoters of the fusion partners, which oftenresult in overexpression. The most common TRK fusions include LMNA-TRKA,TPM3-TRKA, and ETV6-TRKC (Amatu et al., 2016). Hence, genetic eventslead to overexpressed and constitutively active TRK-fusion kinases.These fusions are oncogenic, as shown by their ability to transformmouse embryonic fibroblasts and normal epithelium (Russell et al., 2000;Vaishnavi et al., 2015).

TRK fusion was first reported in a human colon carcinoma, which wasnamed as oneD at that time (Martin-Zanca et al., 1986). Recent advancesin high-throughput RNA sequencing greatly promote the efficiency ofidentifying chromosomal rearrangement events in patient samples.Consequently, TRK fusions have been found across a wide range of humanmalignancies, including but are not limited to non-small rung cancer,colorectal cancer, gastric cancer, low-grade glioma glioblastoma,Spitzoid cancer, soft tissue sarcoma, papillary thyroid carcinoma, headand neck squamous cell carcinoma, congenital fibrosarcoma, congenitalmesoblastic nephroma, secretory breast carcinoma, mammary analoguesecretory carcinoma, acute myeloid leukemia, and ductal carcinoma (Amatuet al., 2016; Khotskaya et al., 2017). The frequency of TRK fusions isrelatively low. For example, approximately 0.5% to 2.7% colon cancersare affected by TRK fusions (Creancier et al., 2015; Lee et al., 2015).However, for certain cancer types, such as secretory breast carcinoma,TRK fusions can be found in the vast majority of cases (Tognon et al.,2002).

TRK mutations and deletions have been observed in additional humandiseases, such as pulmonary neuroendocrine tumors, anhidrosis syndrome,obesity, congenital heart defects, and acute myeloid leukemia (Khotskayaet al., 2017). In addition, TRK amplification are associated withseveral human diseases, such as liver cancer, invasive breast cancer,lung adenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer,ovarian cancer, esophageal cancer, urinary bladder cancer, endometrialcancer, pheochromocytoma, Wilms' tumor, and prostate cancer (Khotskayaet al., 2017).

The never growth factor (NGF) and its main receptor, tropomyosinreceptor kinase A (TRKA), have long been recognized for their roles incentral and peripheral pain (Denk et al., 2017). Nociceptive neuronsexpress TRKA and mediate pain sensation by transmitting pain signals tothe central nervous system, Multiple NGF-neutralizing antibodies, suchas tanezumab, are undergoing clinical assessment in patients withosteoarthritis, lower back pain, cancer pain, neuropathic pain, andother pain conditions (Miller et al., 2017). The efficacy of NGFantibodies in pain relief has been clearly documented in. clinics.However, administration of NGF neutralizing antibodies has been shown toresult in rapidly progressed joint destruction in some patients thatleads to total joint replacement (Schnitzer and Marks, 2015). Theseadverse events may be related to sustained exposure to NGF antibodies.Targeting TRK represents another promising therapeutic strategy blockingthe NGF/TRK signaling pathway for pain management. However, currentlyavailable pan-TRK kinase inhibitors may induce significant on-targetadverse effects through modulating TRK family members in the centralnervous system. Peripherally restricted TRK bifunctional degraders areexpected to selective block the NGF/TRK pathway in peripheral nerveswhile spare these targets in the central nervous system.

TRK is associated with cancer, inflammatory diseases, acute and chronicpain, pruritus, bone-related diseases, neurodegenerative diseases,infectious diseases, and other diseases, including but no limited toneuroblastoma, prostate cancer, pancreatic cancer, melanoma, head andneck cancer, gastric carcinoma, lung carcinoma, liver cancer, uterinecancer, adrenal cancer, biliary tree cancer, intestinal cancer,colorectal cancer, ovarian cancer, lung carcinoma, small cell lungcancer, non-small cell lung cancer, gastric carcinoma, breast cancer,esophageal cancer, urinary bladder cancer, endometrial cancer, braincancer, low-grade glioma, glioblastoma, medulloblastoma, secretorybreast carcinoma, salivary gland cancer, papillary thyroid carcinoma,ductal carcinoma, acute myeloid leukemia, large cell neuroendocrinetumors, pulmonary neuroendocrine tumors, sarcomas, pheochroinocytoma,fibrosarcoma, congenital fibrosarcoma, congenital mesoblastic nephroma,secretory breast carcinoma, malignant fibrous histiocytoma, embryonalrhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma neoplasms of thecentral nervous systems, osteosarcoma, synovial sarcoma, liposarcoma,alveolar soft part sarcoma, Spitzoid cancer, Wilms' tumor, lymphomas(e.g,. including Hodgkin's lymphoma, lymphoplasmacytoid lymphoma,follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantlecell lymphoma, B-lineage large cell lymphoma. Burkitt's lymphoma, andT-cell anaplastic large cell lymphoma), inflammatory lung diseases (e.g.asthma), inflammatory bowel diseases, (e.g. ulcerative colitis, Crohn'sdisease), inflammatory skin diseases (e.g. atopic dermatitis, eczema andpsoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain,cancer pain, surgical pain, inflammatory pain, neuropathic pain,nociceptive pain, pain of osteoarthritis, chronic low back pain, lowback pain of osteoporosis, pain of bone fracture, pain of rheumatoidarthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia,pain of pancreatitis, pain of interstitial cystitis, pain ofendometriosis, pain of irritable bowel syndrome, migraine, pain ofpulpitis, interstitial cystitis pain, painful bladder syndrome, centralpain syndromes, postsurgical pain syndromes, bone and joint pain,repetitive motion pain, dental pain, myofascial pain, perioperativepain, dysmennorhea, myofascial pain, angina pain, headache, primaryhyperalgesia, secondary hyperalgesia, primary allodynia, secondaryallodynia, other pain caused by central sensitization, systemiccutaneous pruritus, localized cutaneous pruritus, senile cutaneouspruritus, gestational pruritus, pruritus ani, vulvar pruritus,metastatic bone disease, treatment-induce bone loss, osteoporosis,rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget'sdisease, periodontal disease, osteolytie disease, multiple sclerosis,Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia,anorexia, demyelination and dysmyelination.

TRK kinase inhibitors are currently undergoing clinical or pre-clinicaldevelopment, including but are not limited to altiratinib (DCC2701,DCC-270, DP-5164) (Smith et al., 2015), sitravatinib (MGCD516)(Patwardhan et al., 2016), cabozantinib (XL-184, BMS-907351) (Fuse etal., 2017), dovitinib (TKI-258, CHIR-258) (Chong et al., 2017),entrectinib (RXDX-101) (Menichincheri et al., 2016), milciclib(PHA-848125AC) (Brasca et al., 2009), belizatinib (TSR-011) (Ricciuti etal., 2017), GZ389988 (Bailey et al., 2017a, b), pegcantratinib (Cranstonet al., 2017), AZD7451 (Tatematsu et al., 2014), larotrectinib(LOXO-101;ARRY-470) (Drilon et al., 2018), TPX-0005 (Cui et al., 2016),LOXO-195 (Blake et al., 2016), regorafenib (Subbiah et al., 2017),DS-6051b (Fujiwara et al., 2018), F17752 (Amato et al., 2016), PLX7486(Amatu et al., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey etal., 2017a, b), VM902A (Bailey et al., 2017a, b), ONO-4474 (Bailey etal., 2017a, b), PF-06273340 (Skerratt et al., 2016) and GNF-8625 (Choiet al., 2015). The most advanced ones are entrectinib and larotrectinib(Khotskaya. et al., 2017). These agents are tested in basket trials thatrecruit patients according to detection of TRK-fusions instead ofhistology. The phase 2 results of larotrectinib demonstrated that mostpatients (75%) responded to the therapy and that 55% patient remainedprogression-free at 1 year (Drilon et al., 2018). Phase 1 results ofentrectinib also recorded marked and durable response in patients withTRK-fusion tumors (Drilon et al., 2017b). The remarkable efficacy of TRKinhibitors was independent of tumor types. These substantial resultscollectively highlight a role of TRK fusions as the sole oncogenicdrivers in a subset of human malignancies, irrespective of tissue oforigin.

Non-specific side effects and the development of resistance to TRKkinase inhibitors remain a challenge in development of effectivetreatments. Thus, new small-molecule targeting TRK's functions throughinhibition and/or degradation will be very useful.

Without wishing to be bound by any theory, the present disclosure isbelieved to be based, at least in part, on the discovery that novelheterobivalent small molecules which degrade TRK, TRK fusion proteins,and/or TRK mutant proteins are useful in the treatment of TRK-mediateddiseases, particularly non-small cell lung cancer, colorectal cancer,gastric cancer, liver cancer, invasive breast cancer, lungadenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer,ovarian cancer, esophageal cancer, urinary bladder cancer, endometrialcancer, prostate cancer, low-grade glioma, glioblastoma, Spitzoidcancers, soft tissue sarcoma, papillary thyroid carcinoma, head and necksquamous cell carcinoma, congenital fibrosarcoma, congenital mesoblasticnephroma, secretory breast carcinoma, mammary analogue secretorycarcinoma, acute myeloid leukemia, ductal carcinoma, pulmonaryneuroendocrine tumors, pheochromocytoma, and Wilms' tumor (Amatu et al.,2016; Khotskaya et al., 2017). The disclosed noval bifunctional TRKdegraders are useful in the treatment of TRK-mediated cancer,inflammatory diseases, acute and chronic pain, pruritus, bone-relateddiseases, neurodegenerative diseases, infectious diseases, and otherdiseases, including but not limited to neuroblastoma, prostate cancer,pancreatic cancer, melanoma, head and neck cancer, gastric carcinoma,lung carcinoma, liver cancer, uterine cancer, adrenal cancer, biliarytree cancer, intestinal cancer, colorectal cancer, ovarian cancer, lungcarcinoma, small cell lung cancer, non-small cell lung cancer, gastriccarcinoma, breast cancer, esophageal cancer, urinary bladder cancer,endometrial cancer, brain cancer, low-grade glioma, glioblastoma,medulloblastoma, secratory breast cancer, secretory breast carcinoma,salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma,adult myeloid leukemia, acute myeloid leukemia, large cellneuroendocrine tumors , pulmonary neuroendocrine tumors, sarcomas,pheochromozytoma, fibrosarcoma, congenital fibrosarcoma, congenitalmesoblastic nephroma, secretory breast carcinoma, malignant fibroushistiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma,neurofibrosarcoma, neoplasms of the central nervous systems,osteosarcoma, synovial sarcoma, liposarcoma alveolar soft part sarcoma,Spitzoid cancer, Wilms' tumor, lymphomas (e.g. including Hodgkin'slymphoma, lymphoplasinacytoid lymphoma, follicular lymphoma,mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoina,B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplasticlarge cell lymphoma), inflammatory lung diseases (e.g. asthma),inflammatory bowel diseases, (e.g. ulcerative colitis, Crohn's disease),inflammatory skin diseases (e.g. atopic dermatitis, eczema andpsoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain,cancer pain, surgical pain, inflammatory pain, neuropathic pain,nociceptive pain, pain of osteoarthritis, chronic low hack pain, lowhack pain of osteoporosis, pain of hone fracture, pain of rheumatoidarthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia,pain of pancreatitis, pain of interstitial cystitis, pain ofendometriosis, pain of irritable bowel syndrome, migraine, pain ofpulpitis, interstitial cystitis pain, painful bladder syndrome, centralpain syndromes, postsurgical pain syndromes, bone and joint pain,repetitive motion pain, dental pain, myofascial pain, perioperativepain, dysmennorhea, myofascial pain, angina pain, headache, primaryhyperalgesia, secondary hyperalgesia, primary allodynia, secondaryallodynia, other pain caused by central sensitization, systemiccutaneous pruritus, localized cutaneous pruritus, senile cutaneouspruritus, gestational pruritus, pruritus ani, vulyar pruritus,metastatic hone disease, treatment-induce bone loss, osteoporosis,rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget'sdisease, periodontal disease, osteolytic disease, multiple sclerosis,Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia,anorexia, demyelination and dysmyelination.

Selective degradation of a target protein induced by a small moleculemay be achieved by recruiting an E3 ubiquitin ligase and mimickingprotein misfolding with a hydrophobic tag (Buckley and Crews, 2014).Additionally, the small molecule has one moiety that binds to an E3ubiquitin ligase and another moiety that binds the protein target ofinterest (Buckley and Crews, 2014). The induced proximity leads toubiquitination of the target followed by its degradation viaproteasome-mediated proteolysis. Several types of high affinitysmall-molecule E3 ligase ligands have been identified or developed. Theyinclude (1) immunomodulatory drugs (IMiDs) such as thalidomide andpomalidomide, which bind cereblon (CRBN or CRL4CRBN), a component of acullin-RING ubiquitin ligase (CRL) complex Bondeson et al., 2015;Chamberlain et al., 2014; Fischer et al., 2014; Ito et al., 2010; Winteret al., 2015); (2) VHL-1, a hydroxyproline-containing ligand, whichbinds van Hippel-Lindau protein (VHL or CRL2VHL), a component of anotherCRL complex (Bondeson et al., 2015; Buckley et al., 2012a; Buckley etal., 2012b; Galdeano et al., 2014; Zengerle et al., 2015), (3) compound7, which selectively binds KEAP1, a component of a CRL3 complex(Davieset al 2016); (4) AMG232, which selectively binds MDM2, a heterodimericRING E3 ligase(Sun et al., 2014); and (5) LCL161, which selectivelybinds 1AP, a homodimeric RING E3 ligase (Ohoka et al., 2017; Okuhira etal., 2011; Shibata et al., 2017). The E3 ligase recruiting bifunctionaldegrader technology has been applied to degradation of several proteintargets (Bondeson et al., 2015; Buckley et al., 2015; Lai et al., 2016;Lu et al., 2015; Winter et at., 2015; Zengerle et al., 2015). Inaddition, a hydrophobic tagging approach, which utilizes a bulky andhydrophobic adatriantyl group, has been developed to mimic proteinmisfolding, leading to the degradation of the target protein byproteasome (Buckley and Crews, 2014). This approach has been applied toselective degradation of the pseudokinase HER3 (Xie et al., 2014). Theinventors have not yet seen any efforts applying any of these approachesto degradation of TRK, TRK mutant, TRK deletion, or TRK fusion proteins.

Currently available small molecules targeting TRK focus on inhibition ofthe kinase activity of TRK. A number of selective small-molecule TRKkinase inhibitors, such as altiratinib (DCC2701, DCC-270, DP-5164)(Smith et al., 2015), sitravatinib (MGCD516) (Patwardhan et al., 2016),cabozantinib (XL-184, BMS-907351) (Fuse et al., 2017), dovitinib(TKI-258, CHIR-258) (Chong et al., 2017), entrectinib (RXDX-101)(Menichincheri et al., 2016), milciclib (PHA-848125AC) (Brasca et al.,2009), belizatinib (TSR-011) (Ricciuti et al., 2017), GZ389988 (Baileyet al., 2017a, b), pegcantratinib (Cranston et al., 2017), AZD7451(Tatematsu et al., 2014), larotrectinib (LOXO-101; ARRY-470) (Drilon etal., 2018), TPX-0005 (Cui et al., 2016), LOXO-195 (Blake et al., 2016),regorafenib (Subbiah et al., 2017), DS-6051b (Fujiwara et al., 2018),F17752(Amatu et al., 2016), PLX7486 (Amato et al., 2016), AZD-6918 (Liet al., 2015), ASP7962 (Bailey et al., 2017a, b), VM902A (Bailey et al.,2017a, b), ONO-4474 (Bailey et al., 2017a, b), PF-06273340 (Skerratt etal., 2016) and GNF-8625 (Choi et al., 2015) have been reported.

In the present disclosure, a novel approach is taken: to developcompounds that directly and selectively modulate not only the kinaseactivity of TRK, but also its protein level. Strategies for inducingprotein degradation include recruiting E3 ubiquitin ligases, mimickingprotein misfolding with hydrophobic tags, and inhibiting chaperones.Such an approach, based on the use of bivalent small molecule compounds,permits more flexible regulation of protein levels in vitro and in vivocompared with techniques such as gene knockout or short hairpinRNA-mediated (shRNA) knockdown. Unlike gene knockout or shRNA knockdown,a small molecule approach further provides an opportunity to study doseand time dependency in a disease model through modulating theadministration routes, concentrations and frequencies of administrationof the corresponding small molecule.

Bivalent Compounds

For the purpose of the present disclosure, the terms “bifunctionalcompound”, “bifunctional degrader”, “bifunctional TRK degrader”,“bivalent compound” and “heterobifunctional compound” are usedinterchangeably.

In some aspects, the present disclosure provides bivalent compoundsincluding a TRK ligand conjugated to a degradation tag, or apharmaceutically acceptable salt or analog thereof. The TRK ligand maybe conjugated to the degradation tag directly or via a linker moiety, incertain embodiments, the TRK ligand may be conjugated to the degradationtag directly. In certain embodiments, the TRK ligand may be conjugatedto the degradation tag via a linker moiety.

As used herein, the terms “tropomyosin receptor kinase ligand” acid “TRKligand”, or “TRK targeting moiety” are to be construed to encompass anymolecules ranging from small molecules to large proteins that associatewith or bind to TRK protein. In certain embodiments, the TRK ligand iscapable of binding to a TRK protein comprising TRK, a TRK mutant, a TRKdeletion, or a TRK fusion protein. The TRK ligand can be, for examplebut not limited to, a small molecule compound (i.e., a molecule ofmolecular weight less than about 1.5 kilodaltons (kDa)), a peptide orpolypeptide, nucleic acid or oligonucleotide, carbohydrate such asoligosaccharides, or an antibody or fragment thereof.

TRK Ligand

The TRK ligand or targeting moiety can be a TRK kinase inhibitor or aportion of TRK kinase inhibitor. In certain embodiments, the TRK kinaseinhibitor comprises one or more of (e.g., altiratinib (DCC2701, DCC-270,DP-5164) (Smith et al., 2015), sitravatinib (MGCD516) (Patwardhan etal., 2016), cabozantinib (XL-184, BMS-907351) (Fuse et al., 2017),dovitinib (TKI-258, CHR-258) (Chong et al., 2017), entrectinib(RXDX-101) (Menichincheri et al., 2016), milciclib (PIA-848125AC)(Brasca et al., 2009), belizatinib (TSR-011) (Ricciuti et al., 2017),GZ389988 (Bailey et al., 2017a, b), pegcantratinib (Cranston et al.,2017), AZD7451 (Tatematsu et al., 2014), larotrectinib (LOXO-101;ARRY-470) (Drilon et al., 2018), TPX-0005 (Cui et al., 2016), LOXO-195(Blake et al., 2016), regorafenib (Subbiah et al., 2017), DS-605 lb(Fujiwara et al., 2018), F17752(Amatu et al., 2016), PLX7486 (Amatu etal., 2016), AZD-6918 (Li et al., 2015). ASP7962 (Bailey et al., 201.7a,h), VM902A (Bailey et al., 2017a,b), ONO-4474 (Bailey et al., 2017a, b),PF-06273340 (Skerratt et al., 2016) and GNF-8625 (Choi et al., 2015),and analogs thereof), which is capable of inhibiting the kinase activityof TRK. As used herein, a “TRK kinase inhibitor” refers to an agent thatrestrains, retards, or otherwise causes inhibition of a physiological,chemical or enzymatic action or function and causes a decrease inbinding of at least 5%. An inhibitor can also or alternately refer to adrug, compound, or agent that prevents or reduces the expression,transcription, or translation of a gene or protein. An inhibitor canreduce or prevent the function of a protein, e.g., by binding to oractivating/inactivating another protein or receptor.

In certain embodiments, the TRK ligand is derived from a TRK kinaseinhibitor comprising:

In certain embodiments, the TRK ligand include, but are, not limited toDS-6051b ((Fujiwara et al., 2018), F17752(Amatu et al., 2016), PLX7486(Amatu et al, 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al.,2017a, b), VM902A (Bailey et al., 2017a, b), PF-06273340 (Skerratt etal., 2016) and ONO-4474 (Bailey et al., 2017a, b). In certainembodiments, the TRK ligand is derived from any one or more of DS-6051b(Fujiwara et al., 2018). F17752(Amatu et al., 2016), PLX7486 (Amatu etal., 2016), AZD-6918 (Li et al., 2015), ASP7962 (Bailey et al., 2017a,b), VM902A (Bailey et at., 2017a,b), PF-06273340 (Skerratt et al., 2016)and ONO-4174 (Bailey et al., 2017a, b).

In another embodiment, the TRK ligand comprises a moiety of Formula 1;

Wherein,

R¹, R², R³, R⁴, Ar, and X are defined as before.

In another embodiment, the TRK ligand comprises a moiety of Formula 1

wherein

X is selected from CR′R″, CO, O, S, SO, SO₂, and NR′, wherein

R′ and R″ are independently selected from hydrogen, halogen, OH,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈ alkylamino, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl,optionally substituted C₃-C₁₀ to cycloalkyl, optionally substitutedC₃-C₁₀ cycloalkoxy, and optionally substituted 3-10 memberedheterocyclyl; or

R′ and R″ together with the atom to which they are connected form anoptionally substituted 3-8 membered cycloalkyl or heterocyclyl ring;

R is selected from optionally substituted C₁-C₈ alkyl, optionallysubstituted C₃-C₁₀ cycloalkyl, optionally substituted 3-10 memberedheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl;

R¹, R², and R³ are independently selected from hydrogen, halogen, CN,NO₂, OR⁵, NR⁷R⁸, COR⁵, CO₂R⁵, C(O)NR⁷R⁸, SOR⁵, SO₂R⁵, SO₂NR⁷R⁸,NR7C(O)R⁸, NR⁵C(O)NR⁷R⁸, NR₇SOR⁸, NR⁷SO₂R⁸, optionally substituted C₁-C₈alkyl, optionally substituted C₁-C₈ alkoxy, optionally substitutedC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl,optionally substituted C₃-C₁₀ cycloalkyl, optionally substituted C₃-C₁₀cycloalkoxy, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₂-C₈ alkenyl, and optionally substituted C₂-C₈alkynyl, wherein

R⁵, R⁶, R⁷, and R⁸ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl,optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substitutedC₃-C₁₀ cycloalkyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted aryl, or optionally substitutedheteroaryl, or

R⁷ and R⁸ together with the atom to which they are connected form anoptionally substituted 4-8 membered heterocyclyl ring;

R⁴ is connected to the linker moiety of the bivalent compound, and isselected from a bond, OR⁹, SR⁹, NR¹⁰R¹¹, COR⁹, CO₂R⁹, CONR¹⁰R¹¹, SOR⁹,SO₂R⁹, SO₂NR¹⁰R¹¹, NR¹⁰COR¹¹, NR⁹CONR¹⁰R¹¹, NR¹⁰SOR¹¹, NR¹⁰SO₂R¹¹,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkoxy, optionally substituted 3-8membered heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, aryl, and optionally substituted heteroaryl,wherein

R⁹, R¹⁰, and R¹¹ are independently selected from null, a bond, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkoxy, optionally substituted 3-8membered heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

R¹⁰ and R¹¹ together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring; and

Ar is selected from aryl and heteroaryl group, each of which isoptionally substituted with one or more substituents independentlyselected from hydrogen, halogen, CN, NO₂, OR¹², SR¹², NR¹³R¹⁴, COR¹²,CO₂R¹², CONR¹³R¹⁴, SOR¹², SO₂R¹², SO₂NR¹³R¹⁴, NR¹³COR¹⁴,NR¹⁵C(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, optionally substituted C₁-C₈alkyl, optionally substituted alkoxy, optionally substitutedC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl,optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₃-C₈cycloalkoxy, optionally substituted 3-8 membered heterocyclyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted aryl, and optionally substitutedheteroaryl, wherein

R¹², R¹³, R¹⁴, and R¹⁵ are independently selected from hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈ alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkoxy, optionally substituted 3-8membered heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

R¹³ and R¹⁴ together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

-   In one embodiment,-   X is selected from CR′R″, O, and NR′, wherein

R′ and R″ are independently selected from hydrogen, F, OH, optionallysubstituted C₁-C₃ alkyl, and optionally substituted C₁-C₃ alkoxy, or

R′ and R″ together with the atom to which they are connected form anoptionally substituted 3-6 membered cycloalkyl or heterocyclyl ring.

In another embodiment, X is selected from CH₂, cyclopropylene, CHF, CF₂,O, NH, NCH₃, NCH₂CH₃, and N-isopropyl.

In another embodiment, R is selected from optionally substituted C₃-C₈cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl.

In another embodiment, R is selected from optionally substituted phenyland optionally substituted heteroaryl.

In another embodiment, X is CH₂; and R is 3,5-difluorophenyl.

In another embodiment, R¹, R², and R³ are independently selected fromhydrogen, F, Cl, and OH.

In another embodiment, R⁴—Ar is selected from a moiety of formulae A1,A2, A3, and A4:

-   wherein-   * indicates the connection to the linker moiety of the bivalent    compound; and-   R^(a) is selected from hydrogen, halogen, CN, NO₂, OR¹², SR¹²,    NR¹³R¹⁴, COR ¹², CO₂R¹², CONR¹³R¹⁴, SOR¹², SO₂R¹², SO₂NR¹³R¹⁴,    NR¹³COR¹⁴, NR¹⁵C(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴, optionally    substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,    optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted    C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted C₃-C₈ cycloalkoxy, optionally substituted 3-8    membered heterocyclyl, optionally substituted C₂-C₈ alkenyl,    optionally substituted C₂-C₈ alkynyl, optionally substituted aryl,    and optionally substituted heteroaryl. wherein

R¹², R¹³, R¹⁴, and R¹⁵ are independently selected from hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkoxy, optionally substituted 3-8membered heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, and optionally substituted heteroaryl, or

R¹³ and R¹⁴ together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, R⁴—Ar is selected from a moiety of formulae A1,A3, A3 and A4:

-   wherein-   * indicates the connection to the linker moiety of the bivalent    compound; and-   R^(a) is selected from hydrogen, halogen, NR¹³R¹⁴, and NR¹³COR¹⁴,    wherein

R¹³ and R¹⁴ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl,optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₃-C₈ cycloalkoxy,optionally substituted 3-8 membered heterocyclyl, optionally substitutedC₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, phenyl, andoptionally substituted C₅-C₆ heteroaryl, or

R¹³ and R¹⁴ together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, R^(a) is (tetrahydro-2H-pyran-4-yl)amino.

In another embodiment, the TRK ligand comprises a moiety of Formula 2;

Wherein,

R¹, R², R³, R⁴, Ar¹, Ar², X, X¹, X², X³, X⁴ and n are defined as before.

In another embodiment, the TRK ligand comprises a moiety of Formula 2:

-   wherein-   X¹, X², X³, and X⁴ are independently selected from C, CR′, and N    (preferly, X¹ is selected from CR′ and-   N, X², X³, and X⁴ are independently selected from C and N), wherein

R′ is selected from hydrogen, halogen, CN, NO₂, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₆cycloalkyl, and optionallysubstituted 3-6 membered heterocyclyl;

-   X is selected from null, a bond, C(R²)₂, C(R²)₂C(R²)₂, CO, C(R²)₂CO,    CONR₂, C(R²)₂O, C(R²)₂NR², and CH₂NR²;-   R¹ and R², at each occurrence, are independently selected from    hydrogen, halogen, OH, NH₂, CN, NO₂, optionally substituted C₁-C₄    alkyl, optionally substituted C₁-C₄ alkoxy, optionally substituted    C₁-C₄ alkylamino, optionally substituted C₁-C₄ alkoxyalkyl,    optionally substituted C₁-C₄ haloalkyl, optionally substituted C₁-C₄    hydroxyalkyl, optionally substituted C₁-C₄alkylaminoC₁-C₄alkyl,    optionally substituted C₃-C₆ cycloalkyl, optionally substituted    C₃-C₆ cycloalkoxy, and optionally substituted 3-6 membered    heterocyclyl;-   n is 1 to 4;-   R³ is connected to the linker moiety of the bivalent compound either    directly or through R⁴;-   R³ and R⁴ are independently selected from null, a bond, OR⁵, SR⁵,    NR⁶R⁷, COR⁵, CO₂R⁵, CONR⁶R⁷, SOR⁵, SO₂R⁵, SO₂NR⁶R⁷, NR⁶COR⁷,    NR⁵C(O)NR⁶R⁷, NR⁶SOR⁷, NR⁶SO₂R⁷, optionally substituted C₁-C₈ alkyl,    optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted    C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl,    optionally substituted C₁-C₈alkylaminoC₁-C₈ alkyl, optionally    substituted C₃-C₈ cycloalkyl, optionally substituted C₃-C₈    cycloalkoxy, optionally substituted 3-8 membered heterocyclyl,    optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈    alkynyl, optionally substituted aryl, and optionally substituted    heteroaryl, wherein

R⁵, R⁶ and R⁷ are independently selected from null, a bond, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₆ cycloalkyl, optionally substituted 3-8 membered heterocyclyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R⁶ and R⁷ together with the atom to which they are connected form a 3-8membered cycloalkyl or 4-8 membered heterocyclyl ring; and

-   Ar¹ and Ar² are independently selected from aryl and heteroaryl,    each of which is optionally substituted with one or more    substituents independently selected from halogen, CN, NO₂, OR¹⁰,    SR¹⁰, NR¹¹R¹², COR¹⁰, CO₂R¹⁰, CONR¹¹R¹², SOR¹⁰, SO₂R¹⁰, SO₂NR¹¹R¹²,    NR¹¹COR¹², NR¹⁰C(O)NR¹¹R¹², NR¹¹SOR¹², NR¹¹SO₂R¹², optionally    substituted C₁-C₈ alkyl, optionally substituted    C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,    optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted    C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₇ cycloalkyl,    optionally substituted 3-7 membered heterocyclyl, optionally    substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl,    optionally substituted aryl, and optionally substituted heteroaryl,    wherein

R¹⁰, R¹¹, and R¹² are independently selected from null, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, or

R¹¹ and R¹² together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

In one embodiment, X¹ is selected from CR′ and N, wherein R′ is selectedfrom hydrogen, F, Cl, CH₃, CF₃, and cyclopropyl.

In another embodiment, X², X³, and X⁴ are independently selected from Cand N.

In another embodiment, X is selected from a bond, CH₂, CH₂CH₂, CO,CH₂CO, CONH, CONCH₃, CH₂O, CH₂NH, and CH₂NCH₃.

In another embodiment, R¹ and R², at each occurrence, are independentlyselected from hydrogen, F, Cl, OH, optionally substituted C₁-C₄ alkyl,optionally substituted C₁-C₄ alkoxy, optionally substituted C₁-C₄alkylamino, optionally substituted C₁-C₄ haloalkyl, optionallysubstituted C₃-C₆ cycloalkyl, optionally substituted C₃-C₆ cycloalkoxy,and optionally substituted 3-6 membered heterocyclyl.

In another embodiment, X is CH₂; and Ar¹ is 3-fluorophenyl.

In another embodiment, R³ is connected to the linker moiety of thebivalent compound directly, and R³ is selected from null, a bond, OR⁵,SR⁵, NR⁶R⁷, COR⁵, CO₂R⁵, CONR⁶R⁷, SOR⁵, SO₂R⁵, SO₂NR⁶R⁷, NR⁶COR₇,NR⁵(O)NR⁶R⁷, NR⁶SOR⁷, NR⁶SO₂R⁷, optionally substituted C₁-C₈ alkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionallysubstituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionallysubstituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl,optionally substituted aryl, and optionally substituted heteroaryl,wherein

R⁵, R⁶ and R⁷ are independently selected from null, a bond, hydrogen,optionally substituted C¹-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₆ cycloalkyl, optionally substituted 3-8 membered heterocyclyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R⁶ and R⁷ together with the atom to which they are connected form a 4-8membered cycloalkyl or heterocyclyl ring.

In another embodiment, R³ is connected to the linker moiety of thebivalent compound through R⁴, and

-   R³ and R⁴ are independently selected from null, a bond, OR⁵, SR⁵,    NR⁶R⁷, COR⁵, CO₂R⁵, CONR⁶R⁷, SOR⁵, SO₂R⁵, SO₂NR⁶R⁷, NR⁶COR⁷,    NR⁵C(O)NR⁶R⁷, NR⁶SOR⁷, NR⁶SO₂R⁷, optionally substituted C₁-C₈ alkyl,    optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted    C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl,    optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally    substituted C₃-C₈ cycloalkyl, optionally substituted 3-8 membered    heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionally    substituted C₂-C₈ alkynyl, optionally substituted aryl, and    optionally substituted heteroaryl, wherein

R⁵, R⁶ and R⁷ are independently selected from null, a bond, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₆ cycloalkyl, optionally substituted 3-8 membered heterocyclyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R⁶ and R⁷ together with the atom to which they are connected form a 4-8membered cycloalkyl or heterocyclyl ring.

In another embodiment,

-   Ar¹ is selected from C₆-C₁₀ aryl and C₅-C₁₀ heteroaryl, each of    which is optionally substituted with one or more substituents    independently selected from F, Cl, CN, NO₂, OR¹⁰, NR¹¹R¹², COR¹⁰,    CO₂R¹⁰, CONR¹¹R¹², SOR¹⁰, SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹COR¹²,    NR¹⁰C(O)NR¹¹R¹², NR¹¹SOR¹², NR¹¹SO₂R¹², optionally substituted C₁-C₆    alkyl, optionally substituted C₁-C₆ alkoxyalkyl, optionally    substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆    hydroxyalkyl, optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl,    optionally substituted C₃-C₇ cycloalkyl, optionally substituted 3-7    membered heterocyclyl, optionally substituted C₂-C₆ alkenyl,    optionally substituted C₂-C₆ alkynyl, optionally substituted aryl,    and optionally substituted C₄-C₅ heteroaryl, wherein

R¹⁰, R¹¹, and R¹² are independently selected from null, hydrogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl. or

R¹¹ and R¹² together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment,

-   Ar² is selected from C₆-C₁₀ aryl and C₅-C₁₀ heteroaryl, each of    which is optionally substituted with one or more substituents    independently selected from F, Cl, CN, NO₂, OR¹⁰, NR¹¹R¹², COR¹⁰,    CO₂R¹⁰, CONR¹¹R¹², SOR¹⁰, SO₂R¹⁰, SO₂NR¹¹NR¹², NR¹¹COR¹²,    NR¹⁰C(O)NR¹¹R¹², NR¹¹SOR¹², NR¹¹SO₂R¹², optionally substituted C₁-C₆    alkyl, optionally substituted C₁-C₆ alkoxyalkyl, optionally    substituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆    hydroxyalkyl, optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl,    optionally substituted C₃-C₇cycloalkyl, optionally substituted 3-7    membered heterocyclyl, optionally substituted C₂-C₆ alkenyl,    optionally substituted C₂-C₆ alkynyl, optionally substituted aryl,    and optionally substituted C₄-C₅heteroaryl, wherein

R¹⁰, R¹¹, and R¹² are independently selected from null, hydrogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, or

R¹¹ and R¹² together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, R³—Ar² is selected from a moiety of formulae B1and B2:

-   wherein-   * indicates the connection to the linker moiety of the bivalent    compound;-   Y¹, Y², Y³, and Y⁴ are independently selected from CH and N, with    the proviso that up to 3 of Y¹, Y², Y³, and Y⁴ are N;-   each R^(a) is independently selected from hydrogen, halogen, CN,    NO₂, OR¹², SR¹², NR¹³R¹⁴, COR¹², CO₂R¹², CONR¹³R¹⁴, SOR¹², SO₂R¹²,    SO₂NR¹³R¹⁴, NR¹³COR¹⁴, NR¹⁵C(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴,    optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈    alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally    substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈    cycloalkyl, optionally substituted C₃-C₈cycloalkoxy, optionally    substituted 3-8 membered heterocyclyl, optionally substituted C₂-C₈    alkenyl, optionally substituted C₂-C₈ alkynyl, optionally    substituted aryl, and optionally substituted heteroaryl, wherein

R¹², R¹³, R¹⁴, and R¹⁵ are independently selected from hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkoxy, optionally substituted 3-8membered heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

R¹³ and R¹⁴ together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring;

-   m is 0 to 4; and-   R³ is the same as defined in Formula 2.

In another embodiment, R³—Ar² is selected from a moiety of formula B3:

-   wherein-   * indicates the connection to the linker moiety of the bivalent    compound;-   Y¹, Y², Y³, and Y⁴ are independently selected from CR^(a), N, O, and    S, with the proviso that up to 3 of Y¹, Y², Y³, and Y⁴ are N;-   each R^(a) is independently selected from hydrogen, halogen, CN,    NO₂, OR¹², SR¹², NR¹³R¹⁴, COR¹², CO₂R¹², CONR¹³R¹⁴, SOR¹², SO₂R¹²,    SO₂NR¹³R¹⁴, NR¹³COR¹⁴, NR¹⁵C(O)NR¹³R¹⁴, NR¹³SOR¹⁴, NR¹³SO₂R¹⁴,    optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈    alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally    substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₃-C₈cycloalkoxy, optionally    substituted 3-8 membered heterocyclyl, optionally substituted C₂-C₈    alkenyl, optionally substituted C₂-C₈ alkynyl, optionally    substituted aryl, and optionally substituted heteroaryl, wherein

R¹², R¹³, R¹⁴, and R¹⁵ are independently selected from hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₃-C₈ cycloalkoxy, optionally substituted 3-8membered heterocyclyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

R¹³ and R¹⁴ together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring;

-   m is 0 to 4; and-   R³ is the same as defined in Formula 2.

In another embodiment, X¹ is N; X² is N; is C; X⁴ is C; X is CH₂; Ar¹ is3-fluorophenyl; and Ar² is 2-pyridyl.

In another embodiment, the TRK ligand comprises a moiety of Formula 3;

-   Wherein,-   R¹, R², R³, R⁴, Ar, X, X¹, X², X³, X⁴ and n are defined as before.-   In another embodiment, the TRK ligand comprises a moiety of FORMULA    3:

-   wherein-   X¹, X², X³, and X⁴ are independently selected from C, CR′, and N    (preferably, X¹ and X⁴ are independently selected from CR′ and N; X²    and X³ are independently selected from C and N), wherein

R′ is selected from hydrogen, halogen, CN, NO₂, and optionallysubstituted C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or 3-6 membered heterocyclyl;

-   X is selected from null, a bond, C(R²)₂, C(R²)₂C(R²)₂, CO, C(R²)₂CO,    NR²CO, OC(R²)₂, and NR²C(R²)₂;-   R¹ and each R² are independently selected from hydrogen, halogen,    OH, NH₂, CN, NO₂, optionally substituted C₁-C₄ alkyl, optionally    substituted C₁-C₄ alkoxy, optionally substituted C₁-C₄ alkylamino,    optionally substituted C₃-C₄ alkoxyalkyl, optionally substituted    C₁-C₄ haloalkyl, optionally substituted C₁-C₄ hydroxyalkyl,    optionally substituted C₁-C₄alkylaminoC₁-C₄alkyl, optionally    substituted C₃-C₆ cycloalkyl, optionally substituted    C₃-C₆cycloalkoxy, and optionally substituted 3-6 membered    heterocyclyl;-   n is 1 to 4;-   R³ is selected from hydrogen, optionally substituted C₁-C₆ alkyl,    optionally substituted C₃-C₆ cycloalkyl, optionally substituted 3-6    membered heterocyclyl, optionally substituted C₃-C₆ alkoxyalkyl,    optionally substituted C₁-C₆haloalkyl, optionally substituted C₁-C₆    hydroxyalkyl, and optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl;-   R⁴ is connected to the linker moiety of the bivalent compound either    directly or through R⁵, wherein R⁴ and R⁵ are independently selected    from null, OR⁶, SR⁶, NR⁷R⁸, COR⁶, CO₂R⁶, CONR⁷R⁸, SOR⁶, SO₂R⁶,    SO₂NR⁷R⁸, NR⁷COR⁸, NR⁹C(O)NR⁷R⁸, NR⁷SOR⁸, NR⁷SO₂R⁸, optionally    substituted C₁-C₈ alkyl, optionally substituted    C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,    optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted    C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted 3-8 membered heterocyclyl, optionally    substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl,    optionally substituted aryl, and optionally substituted heteroaryl,-   wherein

R⁶, R⁷, R⁸, and R⁹ are independently selected from null, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₆ cycloalkyl, optionally substituted 3-8 membered heterocyclyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R⁷ and R⁸ together with the atom to which they are connected form a 4-8membered cycloalkyl or heterocycyl ring;

-   Ar is selected from amyl and heteroaryl, each of which is optionally    substituted with one or more substituents independently selected    from halogen, CN, NO₂, OR¹⁰, SR¹⁰, NR¹¹R¹², COR¹⁰, CO₂R¹⁰,    CONR¹¹R¹², SOR¹⁰, SO₂R¹⁰, SO₂NR¹¹R¹², NR¹⁰COR¹², NR¹⁰C(O)NR¹¹R¹²,    NR¹¹NR¹¹SO₂R¹², optionally substituted C₁-C₈ alkyl, optionally    substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈    haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally    substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₇    cycloalkyl, optionally substituted 3-7 membered heterocyclyl,    optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈    alkynyl, optionally substituted aryl, and optionally substituted    heteroaryl, wherein

R¹⁰, R¹¹, and R¹² are independently selected from null, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ optionally substituted C₃-C₇cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R¹¹ and R¹² together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl rings.

In one embodiment, X¹ and X⁴ is selected from CR′ and N, and R′ isselected from hydrogen, F, Cl, CH₃, CF₃, and cyclopropyl.

In another embodiment, X² and X³ are independently selected from C andN.

In another embodiment, X is selected from a bond, CH₂, CH₂CH₂, CO,CH₂CO, CONH, CONCH₃, CH₂O, CH₂NH, and CH₂NCH₃.

In another embodiment, R¹ and each R² are independently selected fromhydrogen, F, Cl, OH, optionally substituted C₁-C₄ alkyl, optionallysubstituted C₁-C₄ alkoxy, optionally substituted C₁-C₄ alkylamino,optionally substituted C₁-C₄ haloalkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted C₃-C₆ cycloalkoxy, and optionallysubstituted 3-6 membered heterocyclyl.

In another embodiment, R³ is selected from hydrogen, CH₃, CH₂CH₃,propyl, isopropyl, cyclopropyl, CH₂F, CHF₂, and CF₃.

In another embodiment,

-   R⁴ is connected to the linker moiety of the bivalent compound    directly, and-   R⁴ is selected from null, OR⁶, SR⁶, NR⁷R⁸, COR⁶, CO₂R⁶, CONR⁷R⁸, SOR    ⁶, SO₂R⁶, SO₂NR⁷R⁸, NR⁷COR⁸, NR9C(O)NR⁷R⁸, NR⁷SOR⁸, NR⁷SO₂R⁸,    optionally substituted C₁-C₈ alkyl, optionally substituted    C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,    optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted    C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted 3-8 membered heterocyclyl, optionally    substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl,    optionally substituted aryl, and optionally substituted heteroaryl,    wherein

R⁶, R⁷, R⁸, and R⁹ are independently selected from null, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₆ cycloalkyl, optionally substituted 3-8 membered heterocyclyl,optionally substituted heterocyloalkyl, optionally substitutedarylalkyl, heteroarylalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

R7 and R⁸ together with the atom to which they are connected form a 4-8membered cycloalkyl or heterocyclyl ring.

In another embodiment,

-   R⁴ is connected to the linker moiety of the bivalent compound    through R⁵, and-   R⁴ and R⁵ are independently selected from null, OR⁶, SR⁶, NR⁷R⁸,    COR⁶, CO₂R⁶, CONR⁷R⁸, SOR⁶, SO₂R⁶, SO₂NR⁷R⁸, NR⁷COR⁸, NR⁹C(O)NR⁷R⁸,    NR⁷SOR⁸, NR⁷SO₂R⁸, optionally substituted C₁-C₈ alkyl, optionally    substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈    haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl, optionally    substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₈    cycloalkyl, optionally substituted 3-8 membered heterocyclyl,    optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈    alkynyl, optionally substituted aryl, and optionally substituted    heteroaryl,-   wherein

R⁶, R⁷, R⁸, and R⁹ are independently selected from null, hydrogen,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₆cycloalkyl, optionally substituted 3-8 membered heterocyclyl,optionally substituted heterocycloalkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R⁷ and R⁸ together with the atom to which they are connected form a 4-8membered cycloalkyl or heterocyclyl ring.

In another embodiment,

-   Ar is selected from aryl and heteroaryl, each of which is optionally    substituted with one or more substituents independently selected    from F, Cl, CN, NO₂, OR¹⁰, NR¹¹R¹², COR¹⁰, CO₂R¹⁰, CONR¹¹R¹², SOR¹⁰,    SO₂R¹⁰, SO₂NR¹¹R¹², NR¹¹COR¹², NR¹⁰C(O)NR¹¹R¹², NR¹¹SOR¹²,    NR¹¹SO₂R¹², optionally substituted C₁-C₆ alkyl, optionally    substituted C₁-C₆alkoxyalkyl, optionally substituted C₁-C₆    haloalkyl, optionally substituted C₁-C₆ hydroxyalkyl, optionally    substituted C₁-C₆alkylaminoC₁-C₆alkyl, optionally substituted C₃-C₇    cycloalkyl, optionally substituted 3-7 membered heterocyclyl,    optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆    alkenyl, optionally substituted aryl, and optionally substituted    C₄-C₅ heteroaryl, wherein

R¹⁰, R¹¹, and R¹² are independently selected from null, hydrogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, or

R¹¹ and R¹² together with the atom to which they are connected form a4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, the TRK ligand is selected from the groupconsisting of:

Degradation Tag

As used herein, the term “degradation tag” refers to a compound, whichassociates with or binds to an ubiquitin ligase for recruitment of thecorresponding ubiquitination machinery to TRK or is a hydrophobic groupor a tag that leads to misfolding of the TRK protein and subsequentdegradation at the proteasome or loss of function.

In some embodiments, the degradation tag is a moiety selected from thegroup consisting of FORMULAE 5A, 5B, 5C, and 5D:

-   wherein

V, W, and X are independently selected from CR² and N;

Y is selected from CO, CR³R⁴, and N═N;

Z is selected from null, CO, CR⁵R⁶, NR⁵, O, optionally substitutedC₁-C₁₀ alkylene, optionally substituted C₁-C₁₀ alkenylene, optionallysubstituted C₁-C₁₀ alkynylene, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substitutedC₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl; preferly, Z is selected from null, CH₂, CH═CH,C≡C, NH and O;

R¹, and R² are independently selected from hydrogen, halogen, cyano,nitro, optionally substituted C₁-C₆ alkyl, optionally substituted 3 to 6membered carbocyclyl, and optionally substituted 4 to 6 memberedheterocyclyl;

R³, and R⁴ are independently selected from hydrogen, halogen, cyano,nitro, optionally substituted C₁-C₆ alkyl, optionally substituted 3 to 6membered carbocyclyl, and optionally substituted 4 to 6 memberedheterocyclyl; or R³ and R⁴ together with the atom to which they areconnected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl;and

R⁵ and R⁶ are independently selected from null, hydrogen, halogen, oxo,hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₆ alkyl,optionally substituted 3 to 6 membered carbocyclyl, and optionallysubstituted 4 to 6 membered heterocyclyl; or R⁵ and R⁶ together with theatom to which they are connected form a 3-6 membered carbocyclyl, or 4-6membered heterocyclyl.

In some embodiments, the degradation tag is a moiety selected from thegroup consisting of FORMULAE 5A, 5B, 5C, and 5D:

-   wherein,-   V, W, and X are independently selected from CR² and N;-   Y is selected from CO and CH₂;-   Z is selected from CH₂, NH and O;-   R¹ is selected from hydrogen, C₁-C₅ alkyl and halogen; and-   R² is selected from hydrogen, halogen, and C₁-C₅ alkyl.

In one embodiment, the degradation tag is a moiety selected from thegroup consisting of FORMULA 5B and FORMULA 5C.

In some embodiments, the degradation tag is a moiety selected from thegroup consisting of FORMULAE, 5E, 5F, 5F, 5G, 5H, and 5I:

-   wherein

U, V, W, and X are independently selected from CR² and N;

Y is selected from CR³R⁴, NR³ and O; preferly, Y is selected from CH₂,NH, NCH₃ and O;

Z is selected from null, CO, CR⁵R⁶, NR⁵, O, optionally substitutedC₁-C₁₀ alkylene, optionally substituted C₁-C₁₀ alkenylene, optionallysubstituted alkynylene, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, optionally substitutedC₃-C₁₃ spiro heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl; preferly, Z is selected from null, CH₂, CH═CH,C≡C, NH and O;

R¹, and R² are independently selected from hydrogen, halogen, cyano,nitro, optionally substituted C₁-C₆ alkyl., optionally substituted 3 to6 membered carbocyclyl, and optionally substituted 4 to 6 memberedheterocyclyl;

R³, and R⁴ are independently selected from hydrogen, halogen, cyano,nitro, optionally substituted C₁-C₆ alkyl, optionally substituted 3 to 6membered carbocyclyl, and optionally substituted 4 to 6 memberedheterocyclyl; or R³ and R¹ together with the atom to which they areconnected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl;and

R⁵ and R⁶ are independently selected from null, hydrogen, halogen, oxo,hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₆ alkyl,optionally substituted 3 to 6 membered carbocyclyl, and optionallysubstituted 4 to 6 membered heterocyclyl; or R⁵ and R⁶ together with theatom to which they are connected form a 3-6 membered carbocyclyl, or 4-6membered heterocyclyl.

In one embodiment, the degradation tag is a moiety of FORMULA 6A:

-   wherein

R¹ and R² are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl,optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈ aminoalkyl, optionallysubstituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₃-C₇cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionallysubstituted C₂-C₈ alkenyl, and optionally substituted C₂-C₈ alkynyl; and

R³ is hydrogen, optionally substituted C(O)C₁-C₈ alkyl, optionallysubstituted C(O)C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C(O)C₁-C₈haloalkyl, optionally substituted C(O)C₁-C₈ hydroxyalkyl, optionallysubstituted C(O)C₁-C₈ aminoalkyl, optionally substitutedC(O)C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C(O)C₃-C₇cycloalkyl, optionally substituted C(O)(3-7 membered heterocyclyl),optionally substituted C(O)C₂-C₈ alkenyl, optionally substitutedC(O)C₂-C₈ alkenyl, optionally substituted C(O)OC₁-C₈alkoxyC₁-C₈alkyl,optionally substituted C(O)OC₁-C₈ haloalkyl, optionally substitutedC(O)OC₁-C₈ hydroxyalkyl, optionally substituted C(O)OC₁-C₈ aminoalkyl,optionally substituted C(O)OC₁-C₈alkylaminoC₁-C₈alkyl, optionallysubstituted C(O)OC₃-C₇cycloalkyl, optionally substituted C(O)O(3-7membered heterocyclyl), optionally substituted C(O)OC₂-C₈ alkenyl,optionally substituted C(O)OC₂-C₈ alkynyl, optionally substitutedC(O)NC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C(O)NC₁-C₈ haloalkyl,optionally substituted C(O)NC₁-C₈ hydroxyalkyl, optionally substitutedC(O)NC₁-C₈ aminoalkyl, optionally substitutedC(O)NC₁-C₈alkylaminoC₁-C₈alkyl, optionally substitutedC(O)NC₃-C₇cycloalkyl, optionally substituted C(O)N(3-7 memberedheterocyclyl), optionally substituted C(O)NC₂-C₈ alkenyl, optionallysubstituted C(O)NC₂-C₈ alkynyl, optionally substituted P(O)(OH)₂,optionally substituted P(O)(OC₁-C₈alkyl)₂, and optionally substitutedP(O)(OC₁-C₈ aryl)₂.

In one embodiment, the degradation tag is a moiety selected from thegroup consisting of FORMULAE 6B. 6C, 6D, 6E and 6F:

-   wherein

R¹ and R² are independently selected from hydrogen, halogen, OH, NH₂,CN, optionally substituted C₁-C₈ alkyl, optionally substitutedC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈aminoalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionallysubstituted C₃-C₇cycloalkyl, optionally substituted 3-7 memberedheterocyclyl, optionally substituted C₂-C₈ alkenyl, and optionallysubstituted C₂-C₈ alkenyl; (preferably, R¹ is selected from iso-propylor tert-butyl; and R² is selected from hydrogen or methyl);.

R³ is hydrogen, optionally substituted C(O)C₁-C₈ alkyl, optionallysubstituted C(O)C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C(O)C₁-C₈haloalkyl, optionally substituted C(O)C₁-C₈ hydoxyalkyl, optionallysubstituted C(O)C₁-C₈ aminoalkyl, optionally substitutedC(O)C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C(O)C₃-C₇cycloalkyl, optionally substituted C(O)(3-7 membered heterocyclyl),optionally substituted C(O)C₂-C₈ alkenyl, optionally substitutedC(O)C₂-C₈ alkynyl, optionally substituted C(O)OC₁-C₈alkoxyC₁-C₈alkyl,optionally substituted C(O)OC₁-C₈ haloalkyl, optionally substitutedC(O)OC₁-C₈ hydroxyalkyl, optionally substituted (O)OCC₁-C₈ aminoalkyl,optionally substituted C(O)OC₁-C₈alkylaminoC₁-C₈alkyl, optionallysubstituted C(O)OC₃-C₇ cycloalkyl, optionally substituted C(O)O(3-7membered heterocyclyl), optionally substituted C(O)OC₂-C₈ alkenyl,optionally substituted C(O)OC₂-C₈ alkynyl, optionally substitutedC(O)NC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C(O)NC₁-C₈ haloalkyl,optionally substituted C(O)NC₁-C₈ hydroxyalkyl, optionally substitutedC(O)NC₁-C₈ aminoalkyl, optionally substitutedC(O)NC₁-C₈alkylaminoC₁-C₈alkyl, optionally substitutedC(O)NC₃-C₇cycloalkyl, optionally substituted C(O)N(3-7 memberedheterocyclyl), optionally substituted C(O)NC₂-C₈ alkenyl, optionallysubstituted C(O)NC₂-C₈ alkynyl, optionally substituted P(O)(OH)₂,optionally substituted P(O)(OC₁-C₈ alkyl)₂, and optionally substitutedP(O)(OC₁-C₈ aryl)₂; and

R⁴ and R⁵ are independently selected from hydrogen, COR⁶, CO₂R⁶,CONR⁶R⁷, SOR⁶, SO₂R⁶, SO₂NR⁶R⁷, optionally substituted C₁-C₈ alkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-8 memberedcycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, wherein

R⁶ and R⁷ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₁-C₈ alkoxy, optionallysubstituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-8 memberedcycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

R4 and R⁵; R⁶ and R⁷ together with the atom to which they are connectedform a 4-8 membered cycloalkyl or heterocyclyl ring;

Ar is selected from aryl and heteroaryl, each of which is optionallysubstituted with one or more substituents independently selected from F,Cl, CN, NO₂, OR⁸, NR⁸R⁹, COR⁸, CO₂R⁸, CONR⁸R⁹, SOR⁸, SO₂R⁸, SO₂NR⁹R¹⁰,NR⁹COR¹⁰, NR⁸C(O)NR⁹R¹⁰, NR⁹SOR¹⁰, NR⁹SO₂R¹⁰, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxyalkyl, optionallysubstituted C₁-C₆ haloalkyl, optionally substituted C₁-C₆ hydroxyalkyl,optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally substituted aryl, and optionally substituted C₄-C₅heteroaryl, wherein

R⁸, R⁹, and R¹⁰ are independently selected from null, hydrogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted 3-7 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, or

R⁸ and R⁹; R⁹ and R¹⁰ together with the atom to which they are connectedform a 4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, the degradation tag is a moiety of FORMULA 7A:

wherein V, W, X, and Z are independently selected from CR⁴ and N.

R¹, R², R³, and R⁴ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈ alkyl,optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₃-C₇ cycloalkyl, optionallysubstituted 3-7 membered heterocyclyl, optionally substituted C₂-C₈alkenyl, and optionally substituted C₂-C₈alkynyl.

In another embodiment, the degradation tag is a moiety of FORMULA 7B:

wherein

R¹, R², and R³ are independently selected from hydrogen, halogene,optionally substituted C₁-C₈ alkyl, optionally substitutedC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ hydroxyalkyl, optionally substituted C₃-C₇cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionallysubstituted C₂-C₈ alkenyl, and optionally substituted C₂-C₈ alkynyl;

R⁴ and R⁵ are independently selected from hydrogen, COR⁶, CO₂R⁶,CONR6R⁷, SOR⁶, SO₂R⁶, SO₂NR⁶R⁷, optionally substituted C₁-C₈ alkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted aryl-C₁-C₈ alkyloptionally substituted 3-8 membered cycloalkyl, optionally substituted3-8 membered heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, wherein

R⁶ and R⁷ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl,optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted3-8 membered cycloalkyl, optionally substituted 3-8 memberedheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl, or

R⁶ and R⁷ together with the atom to which they are connected form a 4-8membered cycloalkyl or heterocyclyl ring.

In another embodiment, the degradation tag is derived from any of thefollowing:

In certain embodiments, the degradation tag is an E3 ligase. In certainembodiments, the degradation tag comprises one or more of cereblon E3ligase, a VHL E3 ligase, a MDM2 ligase, a TRIM24 ligase, a TRIM21ligase, a KEAP 1 ligase, and an IAP ligase. In certain embodiments, thedegradation tags of the present disclosure include, e.g., pomalidomide(Fischer et al., 2014), thalidomide (Fischer et al., 2014), lenalidomide(Fischer et al., 2014), VH032 (Galdeano et al., 2014; Maniaci et al.,2017), adamantane (Xie et al., 2014),1((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane (E. Wakeling, 1995),nutlin-3a (Vassilev et al., 2004), RG7112 (Vu et al., 2013), RG7338, AMG232 (Sun et al., 2014), AA-115 (Aguilar et al., 2017), bestatin(Hiroyuki Suda et al., 1976), MV1 (Varfolomeev et al., 2007), LCL161(Weisberg et al., 2010), and/or analogs thereof. In certain embodiments,the degradation tag is derived from a compound comprising pomalidomide(Fischer et al., 2014), thalidomide (Fischer et al., 2014), lenalidomide(Fischer et al., 2014), VH032 (Galdeano et al., 2014; Maniaci et al.,2017), adamantane (Xie et al., 2014),1((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane (E. Wakeling, 1995),nutlin-3a (Vassilev et al., 2004), RG7112 (Vu et al., 2013), RG7338, AMG232 (Sun et al., 2014), AA-115 (Aguilar et al., 2017), bestatin(Hiroyuki Suda et al., 1976), MV1 (Varfolomeev et al., 2007), LCL161(Weisberg et al., 2010), and/or analogs thereof.

In another embodiment, the degradation tag is selected from the groupconsisting of:

Linker Moiety

As used herein, a “linker” or “linker moiety” is a bond, molecule, orgroup of molecules that binds two separate entities to one another.Linkers provide for optimal spacing of the two entities. The term“linker” in some aspects refers to any agent or molecule that bridgesthe TRK ligand to the degradation tag. One of ordinary skill in the artrecognizes that sites on the TRK ligand or the degradation tag, whichare not necessary for the function of the degraders of the presentdisclosure, are ideal sites for attaching a linker, provided that thelinker, once attached to the conjugate of the present disclosures, doesnot interfere with the function of the TRK ligand, i.e., its ability tobind TRK, or the function of the degradation tag, i.e., its ability torecruit a ubiquitin ligase.

The length of the linker of the bivalent compound can be adjusted tominimize the molecular weight of the bivalent compounds, avoid the clashof the TRK ligand or targeting moiety with the ubiquitin ligase and/orinduce TRK misfolding by the hydrophobic tag. In certain embodiments,the linker comprises acyclic or cyclic saturated or unsaturated carbon,ethylene glycol, amide, amino, ether, urea, carbamate, aromatic,heteroaromatic, heterocyclic or carbonyl groups. In certain embodiments,the length of the linker is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20 or more atoms.

In some embodiments, the linker moiety is of FORMULA 9:

-   wherein

A, W and B, at each occurrence, are independently selected from null, orbivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)N(R¹)R″,R′C(S)N(R¹)R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R¹)R″, R′SR″,R′SOR″, R′SO₂R″, R′SO₂N(R¹)R″, R′N(R¹)R″, R′NR¹COR, R′NR¹C(O)OR″,R′N¹CON(R²)R″, R′NR¹C(S)R″, R″NR″S(O)R″, R′NR¹S(O)₂R″, andR′NR¹S(O)₂N(R²)″, wherein

R′ and R″ are independently selected from null, optionally substitutedR^(r)—(C₁-C₈ alkyl), or a moiety comprising of optionally substitutedC₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈ alkynylene, optionallysubstituted C₁-C₈ hydroxyalkylene, optionally substitutedC₁-C₈alkoxyC₁-C₈alkylene, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈ haloalkylene,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fusedcycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionallysubstituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl,optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl;

R^(r) is selected from optionally substituted 3-10 membered carbocyclyl,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fusedheterocyclyl, optionally substituted C₃-C₁₃ bridged cycloalkyl,optionally substituted C₃-C₁₃ bridged heterocyclyl, optionallysubstituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiroheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl;

R¹ and R² are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl,optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionallysubstituted C₁-C₈ hydroxalkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R¹ and R², R′and R¹, R′ and R², R″ and R¹, R″ and R² togetherwith the atom to which they are connected form a 3-20 memberedcycloalkyl or 4-20 membered heterocyclyl ring; and m is 0 to 15.

In some embodiments, the linker moiety is of FORMULA 9:

-   wherein

A, W, and B, at each occurrence, are independently selected from null,CO, CO₂, C(O)NR¹, C(S)NR¹, O, S, SO, SO₂, SO₂NR¹, NR¹, NR¹CO, NR¹CONR²,NR¹C(S), optionally substituted C₁-C₈ alkyl, optionally substitutedC₁-C₈ alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionallysubstituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₃-C₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, and optionallysubstituted C₃-C₁₃ spiro heterocyclyl, wherein

R¹ and R² are independently selected from hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl,optionally substituted C₃-C₆cycloalkoxy, optionally substituted 3-6membered heterocyclyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted C₁-C₆ alkoxyalkyl, optionally substituted C₁-C₆ haloalkyl,optionally substituted C₁-C₆ hydroxyalkyl , optionally substituted C₁-C₆alkylamino, and optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl; and

m is 0 to 15.

In one embodiment, the linker moiety is of FORMIULA 9A:

Wherein R¹, R², R³ and R⁴, at each occurrence, are independentlyselected from hydrogen, halogen, hydroxyl, amino, cyano, nitro,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxyalkyl, optionallysubstituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl ,optionally substituted C₁-C₈ alkylamino, and optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionallysubstituted 3-10 membered carbocyclylamino, optionally substituted 4-8membered membered heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl, or

R¹ and R², R³ and R⁴ together with the atom to which they are connectedform a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

A, W and B, at each occurrence, are independently selected from null, orbivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)N(R⁵)R″,R′C(S)N(R⁵)R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR⁵R″, R′SR″, R′SOR″,R′SO₂R″, R′SO₂N(R⁵)R″, R′N(R⁵)R″, R′NR⁵COR″, R′NR⁵C(O)OR″,R′NR⁵CON(R⁵)R″, R′NR⁵C(S)R″, R′NR⁵S(O)R″, R′NR⁵S(O)₂R″, andR′NR⁵S(O)₂N(R⁶)R″, wherein

R′ and R″ are independently selected from null, optionally substitutedR^(r)—(C₁-C₈ alkyl), or a moiety comprising of optionally substitutedC₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈ alkynylene, optionallysubstituted C₁-C₈ hydroxyalkylene, optionally substitutedC₁-C₈alkoxyC₁-C₈alkylene, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈ haloalkylene,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fusedcycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionallysubstituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl,optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl;

R^(r) is selected from optionally substituted 3-10 membered carbocyclyl,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fusedheterocyclyl, optionally substituted C₃-C₁₃ bridged cycloalkyl,optionally substituted C₃-C₁₃ bridged heterocyclyl, optionallysubstituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C3-C13 spiroheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl;

R⁵ and R⁶ are independently selected from hydrogen, optionallysubstituted C₁-C₈alkyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ alkoxyalkyl,optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl;

R′ and R″, R⁵ and R⁶, R′ and R⁵, R′ and R⁶, R″ and R⁵, R″ and R⁶together with the atom to which they are connected form a 3-20 memberedcycloalkyl or 4-20 membered heterocyclyl ring;

m is 0 to 15;

n, at each occurrence, is 0 to 15; and

o is 0 to 15.

In one embodiment, the linker moiety is of FORMULA 9A:

-   wherein

R¹, R², R³, and R⁴, at each occurrence, are independently selected fromhydrogen, halogen, CN, OH, NH₂, optionally, substituted C₁-C₆ alkyl,optionally substituted C₃-C₆ cycloalkyl, optionally substituted C₃-C₆cycloalkoxy, optionally substituted 3-6 membered heterocyclyl,optionally substituted C₁-C₆ alkoxy, optionally substituted C₁-C₆alkoxyalkyl, optionally substituted C₁-C₆ haloalkyl, optionallysubstituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆ alkylamino,and optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl;

A, W, and B, at each occurrence, are independently selected from null,CO, CO₂, C(O)NR⁵, C(S)NR:⁵, O, S, SO, SO₂, SO₂NR⁵, NR⁵, NR⁵CO, NR⁵CONR⁶,NR⁵C(S), optionally substituted C₁-C₈ alkyl, optionally substitutedC₁-C₈ alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionallysubstituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₃-C₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, and optionallysubstituted C₃-C₁₃ spiro heterocyclyl, wherein

R⁵ and R⁶ are independently selected from hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl,optionally substituted C₃-C₆ cycloalkoxy, optionally substituted 3-6membered heterocyclyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted C₁-C₆ alkoxyalkyl, optionally substituted C₁-C₆ haloalkyl,optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆alkylamino, and optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl;

m is 0 to 15;

each n is 0 to 15; and

o is 0 to 15.

In another embodiment, the linker moiety is of FORMULA 9B:

-   wherein

R¹ and R², at each occurrence, are independently selected from hydrogen,halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C₁-C₈alkyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈alkoxy C₁-C₈ alkyl, optionally substituted C₁-C₈ haloalkyl, optionallysubstituted C₁-C₈ hydroxyalkyl, optionally substituted C₁-C₈ alkylamino,C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionallysubstituted 3-10 membered carbocyclylamino, optionally substituted 4-10membered heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

R¹ and R² together with the atom to which they are connected form a 3-20membered cycloalkyl or 4-20 membered heterocyclyl ring;

A and B, at each occurrence, are independently selected from null, orbivalent moiety selected from R′—R″, R′CO₂R″, R′C(O)NR³R″, R′C(S)NR³R″,R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R³)R″, R′SR″, R′SOR″, R′SO₂R″,R′SO₂N(R³)R″, R′N(R³)R″, R′NR³COR″, R′NR³C(O)OR″, R′NR³CON(R⁴)R′,R′NR³C(S)R″, R′NR³S(O)R″, R′NR³S(O)₂R″, and R′NR³S(O)₂N(R⁴)R″, wherein

R′ and R″ are independently selected from null, optionally substitutedR^(r)—(C₁-C₈ alkyl), or a moiety comprising of optionally substitutedC₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈ alkynylene, optionallysubstituted C₁-C₈ hydroxyalkylene, optionally substitutedC₁-C₈alkoxyC₁-C₈alkylene, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈ haloalkylene,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fusedcycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionallysubstituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro cycloalkyl,optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl;

R^(r) is selected from optionally substituted 3-10 membered carbocyclyl,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fusedheterocyclyl, optionally substituted C₃-C₁₃ bridged cycloalkyl,optionally, substituted C₃-C₁₃ bridged heterocyclyl, optionallysubstituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiroheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl;

R³ and R⁴ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl,optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionallysubstituted C₁-C₈ hydroxyalkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R³ and R⁴, R′ and R³, R′ and R⁴, R″ and R³, R″ and R⁴together with the atom to which they are connected form a 3-20 memberedcycloalkyl or 4-20 membered heterocyclyl ring;

each m is 0 to 15; and

n is 0 to 15,

In another embodiment, the linker moiety is of FORMULA 9B:

-   wherein

each R¹, and each R² are independently selected from hydrogen, halogen,CN, OH, NH₂, and optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₆ cycloalkyl, optionally substituted C₃-C₆ cycloalkoxy,optionally substituted 3-6 membered heterocyclyl, optionally substitutedC₁-C₆ alkoxy, optionally substituted C₁-C₆ alkoxyalkyl, optionallysubstituted C₁-C₆haloalkyl, optionally substituted C₁-C₆ hydroxyalkyl,optionally substituted C₁-C₆ alkylamino, or C₁-C₆alkylaminoC₁-C₆alkyl;

each A and each B are independently selected from null, CO, CO₂,C(O)NR³, C(S)NR³, O, S, SO, SO₂, SO₂NR³, NR³, NR³CO, NR³CONR⁴, NR³C(S),and optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₈alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionallysubstituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₃-C₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, or C₃-C₁₃ spiroheterocyclyl, wherein

R³ and R⁴ are independently selected from hydrogen, and optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₆cycloalkyl,optionally substituted C₃-C₆ cycloalkoxy, optionally substituted 3-6membered heterocyclyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted C₁-C₆ alkoxyalkyl, optionally substituted C₁-C₆ haloalkyl,optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆alkylamino, or C₁-C₆alkylaminoC₁-C₆alkyl;

each m is 0 to 15; and

n is 0 to 15.

In another embodiment, in FORMULA 9B, m is 1 to 15.

In another embodiment, in FORMULA 9B, n is 1.

In another embodiment, in FORMULA 9B, R¹ and R² are independentlyselected from hydrogen, and optionally substituted C₁-C₈ alkyl.

In another embodiment, the linker moiety is of FORMULA 9C:

-   wherein

X is selected from O, NH, and NR⁷;

R¹, R², R³, R⁴, R⁵, and R⁶, at each occurrence, are independentlyselected from hydrogen, halogen, hydroxyl, amino, cyano, nitro,optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₁-C₈ alkoxy, optionally substituted C₁-C₈ alkoxy C₁-C₈ alkyl,optionally substituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈ alkylamino, optionallysubstituted C₁-C₈ alkylaminoC₁-C₈ alkyl, optionally substituted 3-10membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl;

A and B are independently selected from null, or bivalent moietyselected from R′—R″, R′COR″, R′CO₂R″, R′C(O)N(R⁸)R″, R′C(S)N(R⁸)R″,R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R⁸)R″, R′SR″, R′SOR″, R′SO₂R″,R′SO₂N(R⁸)R′, R′N(R⁸)R″, R′NR⁸COR″, R′NR⁸C(O)OR″, R′NR⁸CON(R⁹)R″, R′NR⁸C(S)R″, R′NR⁸S(O)R″, R′NR⁸S(O)₂R″, and R′NR⁸S(O)₂N(R⁹)R″, wherein

R′ and R″ are independently selected from null, optionally substitutedR^(r)—(C₁-C₈ alkyl), or a moiety comprising of optionally substitutedC₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionallysubstituted C₂-C₈ alkynyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈ haloalkyl,optionally substituted C₁-C₈ alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈ alkynylene, optionallysubstituted C₁-C₈ hydroxyalkylene, optionally substitutedC₁-C₈alkoxyC₁-C₈ alkylene, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈ haloalkylene,optionally substituted 3-10 membered carbocyclyl, optionally substituted4-10 membered heterocyclyl, optionally substituted C₃-C₁₃ fusedcycloalkyl, optionally substituted C₃-C₁₃ fused heterocyclyl, optionallysubstituted C₃-C₁₃ bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃ spiro cycloalkyl,optionally substituted C₃-C₁₃ spiro heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl;

R^(r) is selected from optionally substituted 3-10 membered carbocyclyl,optionally substituted 4-10 membered heterocyclyl, optionallysubstituted C₃-C₁₃ fused cycloalkyl, optionally substituted C₃-C₁₃ fusedheterocyclyl, optionally substituted C₃-C₁₃ bridged cycloalkyl,optionally substituted C₃-C₁₃ bridged heterocyclyl, optionallysubstituted C₃-C₁₃ spiro cycloalkyl, optionally substituted C₃-C₁₃ spiroheterocyclyl, optionally substituted aryl, and optionally substitutedheteroaryl;

R⁷, R⁸ and R⁹ are independently selected from hydrogen, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl,optionally substituted C₂-C₈ alkynyl, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈ haloalkyl, optionallysubstituted C₁-C₈ hydroxyalkyl, optionally substitutedC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 memberedcarbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R⁸ and R⁹, R′ and R⁸, R′ and, R⁹, R″ and R⁸, R″ and R⁹together with the atom to which they are connected form a 3-20 memberedcycloalkyl or 4-20 membered heterocyclyl ring;

m, at each occurrence, is 0 to 15;

n, at each occurrence, is 0 to 15;

o is 0 to 15; and

p is 0 to 15.

In another embodiment, the linker moiety is of FORMULA 9C:

-   wherein

X is selected from O, NH, and NR⁷;

R¹, R², R³, R⁴, R⁵, and R⁶, at each occurrence, are independentlyselected from hydrogen, halogen, CN, OH, NH₂, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl, optionallysubstituted C₃-C₆ cycloalkoxy, optionally substituted 3-6 memberedheterocyclyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted C₁-C₆ alkoxyalkyl, optionally substituted C₁-C₆ haloalkyl,optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆alkylamino, and optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl;

A and B, at each occurrence, are independently selected from null, CO,CO₂, C(O)NR⁷, C(S)NR⁷, O, S, SO, SO₂, SO₂NR⁷, NR⁷, NR⁷CO, NR⁷CONR⁸,NR⁷C(S), optionally substituted C₁-C₈ alkyl, optionally substitutedC₁-C₈ alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionallysubstituted C₁-C₈ haloalkyl, optionally substituted C₁-C₈ hydroxyalkyl,optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₃-C₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₁₃ fused cycloalkyl, optionally substitutedC₃-C₁₃ fused heterocyclyl, optionally substituted C₃-C₁₃ bridgedcycloalkyl, optionally substituted C₃-C₁₃ bridged heterocyclyl,optionally substituted C₃-C₁₃ spiro cycloalkyl, and optionallysubstituted C₃-C₁₃ spiro heterocyclyl, wherein

R⁷ and R⁸ are independently selected from hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl,optionally substituted C₃-C₆ cycloalkoxy, optionally substituted 3-6membered heterocyclyl, optionally substituted C₁-C₆ alkoxy, optionallysubstituted C₁-C₆ alkoxyalkyl, optionally substituted C₁-C₆ haloalkyl,optionally substituted C₁-C₆ hydroxyalkyl, optionally substituted C₁-C₆alkylamino, and optionally substituted C₁-C₆alkylaminoC₁-C₆alkyl;

each m is 0 to 15;

each n is 0 to 15;

o is 0 to 15; and

p is 0 to 15.

In one embodiment, in FORMULA 9C, m and n is 1, and p is 1 to 15;

In one embodiment, in FORMULA 9C, X is selected from O and NH;

In one embodiment, in FORMULA 9C, R¹, R², R³, R⁴, R⁵, and R⁶, areindependently selected from hydrogen, optionally substituted C₁-C₆alkyl.

In another embodiment, the linker moiety comprises a ring selected fromthe group consisting of a 3 to 13 membered ring, a 3 to 13 memberedfused ring, a 3 to 13 membered bridged ring, and a 3 to13 membered spiroring.

In another embodiment, the linker moiety comprises a ring selected fromthe group consisting of Formula C1, C2, C3, C4 and C5:

In one embodiment, A, B and W, at each occurrence, are independentlyselected from null, CO, NH, NH—CO, CO—NH, CH₂—NH—CO, CH₂—CO—NH,NH—CO—CH₂, CO—NH—CH₂, CH₂—NH—CH₂—CO—NH, CH₂—NH—CH₂—NH—CO,NH—CO—CH₂—NH—CH₂CO—NH—CH₂—NH—CH₂, and CH₂—NH—CH₂, R_(r)—CO, R_(r)—NH,R_(r)—NH—CO, R_(r)—CO—NH, R_(r)—CH₂—CO—NH, R_(r)—NH—CO—CH₂,R_(r)—CO—NH—CH₂, R_(r)—CH₂—NH—CH₂—CO—NH, R_(r)—CH₂—NH—CH₂—NH—CO,R_(r)—NH—CO—CH₂—NH—CH₂, R_(r)—CO—NH—CH₂—NH—CH₂, R_(r)—CH₂—NH—CH₂.

In one embodiment, R^(r) is of Formula C1, C2, C3, C4 or C5.

In one embodiment, R^(r) is selected from

In another embodiment, the length of the linker is 0 to 40 linear atoms.

In another embodiment, the length of the linker is 0 to 20 linear atoms.

In another embodiment, the length of the linker is 0 to 8 linear atoms.

In another embodiment, the linker is selected from —(CO)—(CH₂)₁₋₈—,—(CH₂)₁₋₉—, —(CH₂)₁₋₂—(CO)—NH—(CH₂)₂₋₉—,—(CH₂)₁₋₂—(CO)—NH—(CH₂)₁₋₃—(OCH₂CH₂)—(CH₂)₀₋₁—(CO)—(CH₂)₁₋₃—(OCH₂CH₂)₁₋₇,—(CO)—(CH₂)₀₋₃-(alkenylene)-(CH₂)₀₋₃—,—(CO)—(CH₂)₀₋₃-(alkynylene)-(CH₂)₀₋₃-, —(CO)—(CH₂)₀₋₃-(3-8 memberedcarbocyclyl)-(CH₂)₀₋₃—, —(CO)—(CH₂)₀₋₃-(3-8 memberedheterocarboxyclyl)-(CH₂)₀₋₃—, —(CH₂))₀₋₃-(alkenylene)-(CH₂)₀₋₃—,—(CH₂)₀₋₃-(alkynylene)-(CH₂)₀₋₃—, —(CH₂)₀₋₃-(3-8 memberedcarbocyclyl)-(CH₂)₀₋₃—, and —(CH₂)₀₋₃(3-8 memberedheterocarbocyclyl)-(CH₂)₀₋₃—;

R^(r)—(CO)—(CH₂)₁₋₈—, R^(r)—(CH₂)₁₋₉—, R^(r)—(CH₂)₁₋₂—(CO)—NH—(CH₂)₂₋₉—,R^(r)—(CH₂)₁₋₂—(CO)—NH—(CH₂)₁₋₃—(OCH₂CH₂)₁₋₇—,R_(r)—(CH₂)₀₋₁—(CO)—(CH₂)₁₋₃—(OCH₂CH₂)₁₋₇—,R^(r)—(CO)—(CH₂)₀₋₃-(alkenylene)-(CH₂)₀₋₃-,R^(r)—(CO)—(CH₂)₀₋₃-(alkynylene)-(CH₂)₀₋₃—, R^(r)—(CO)—(CH₂)₀₋₃-(3-8membered carbocyclyl)-(CH₂)₀₋₃—, R_(r)-—CO)—(CH₂)₀₋₃-(3-8 memberedheterocarbocyclyl)-(CH₂)₀₋₃—, R^(r)-(CH₂)₀₋₃-(alkenylene)-(CH₂)₀₋₃—,R^(r)—(CH₂)₀₋₃-(alkynylene)-(CH₂)₀₋₃—, R^(r)—(CH₂)₀₋₃-(3-8 memberedcarbocyclyl)-(CH₂)₀₋₃—, and R^(r)—(CH₂)₀₋₃-(3-8 memberedheterocarbocyclyl)-(CH₂)₀₋₃—.

Without wishing to be bound by any particular theory, it is contemplatedherein that, in some embodiments, attaching pomalidomide or VHL-1 toeither portion of the molecule can recruit the cereblon E3 ligase or VHLE3 ligase to TRK.

The bivalent compounds disclosed herein can selectively affectTRK-mediated disease cells compared to WT (wild type) cells (i.e., anbivalent compound able to kill or inhibit the growth of an TRK-mediateddisease cell while also having a relatively low ability to lyse orinhibit the growth of a WT cell), e.g., possess a GI₅₀ for one or moreTRK-mediated disease cells more than 1.5-fold lower, more than 2-foldlower, more than 2.5-fold lower, more than 3-fold lower, more than4-fold lower, more than 5-fold lower, more than 6-fold lower, more than7-fold lower, more than 8-fold lower, more than 9-fold lower, more than10-fold lower, more than 15-fold lower, or more than 20-fold lower thanits GI₅₀ for one or more WT cells, e.g., WT cells of the same speciesand tissue type as the TRK-mediated disease cells.

In some aspects, provided. herein is a method for identifying a bivalentcompound which mediates degradation or reduction of TRK, the methodcomprising: providing a heterobifunctional test compound comprising anTRK ligand conjugated to a degradation tag through a linker; contactingthe heterobifunctional test compound with a cell comprising a ubiquitinligase and TRK; determining whether TRK level is decreased in the cell,and identifying the heterobifunctional test compound as a bivalentcompound which mediates degradation or reduction of TRK. In certainembodiments, the cell is a cancer cell. In certain embodiments, thecancer cell is a TRK-mediated cancer cell.

Cross-Reactivity with Protein Kinases

In some aspects, the TRK ligand can be bound to TRK, TRK fusionproteins, and/or TRK mutant proteins. In some aspects, the TRK ligandcan be bound to ROS1, ROS1 fusion proteins, and/or ROS1 mutant proteins.In some aspects, the TRK ligand can be bound to ALK, ALK fusionproteins, and/or ALK mutant proteins. In some aspects. the TRK ligandcan be bound to TRK, ROS1, or ALK. In some aspects, the TRK ligand canbe bound to TRK or ROS1. In some aspects, the TRK ligand can be bound toTRK or ALK. In some aspects, the TRK ligand can be bound to ROS1 or ALK.

Synthesis and Testing of Bivalent Compounds

The binding affinity of novel synthesized bivalent compounds can beassessed using standard. biophysical assays known in the art (e.g.,isothermal titration calorimetry (ITC), surface plasmon resonance(SPR)). Cellular assays can then be used to assess the bivalentcompound's ability to induce TRK degradation and inhibit cancer cellproliferation. Besides evaluating a bivalent compound's induced changesin the protein levels of TRK, TRK mutants, or TRK fusion proteins,enzymatic activity can also be assessed. Assays suitable for use in anyor all of these steps are known in the art, and include, e.g., westernblotting, quantitative mass spectrometry (MS) analysis, flow cytometry,enzymatic activity assay, ITC, SPR, cell growth inhibition, xenograftorthotopic, and patient-derived xenograft models. Suitable cell linesfor use in any or all of these steps are known in the art and include,cancer cell lines: 1); KM12, 2); CUTO3.29, 3); MO91, 4); HEL, Suitablemouse models for use in any or all of these steps are known in the artand include subcutaneous xenograft models, orthotopic models,patient-derived xenograft models, and patient-derived orthotopic models.

By way of non-limiting example, detailed synthesis protocols aredescribed in the Examples for specific exemplary bivalent compounds.

Pharmaceutically acceptable isotopic variations of the compoundsdisclosed herein are contemplated and can be synthesized usingconventional methods known in the art or methods corresponding to thosedescribed in the Examples (substituting appropriate reagents withappropriate isotopic variations of those reagents). Specifically, anisotopic variation is a compound in which at least one atom is replacedby an atom having the same atomic number, but an atomic mass differentfrom the atomic mass usually found in nature. Useful isotopes are knownin the art and include, for example, isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. Exemplaryisotopes thus include, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³⁵S,¹⁸F, and ³⁶Cl.

Isotopic variations (e.g., isotopic variations containing ²H) canprovide therapeutic advantages resulting from greater metabolicstability, e.g., increased in vivo half-life or reduced dosagerequirements. In addition, certain isotopic variations (particularlythose containing a radioactive isotope) can be used in drug or substratetissue distribution studies. The radioactive isotopes tritium (³H) andcarbon-14 (¹⁴C) are particularly useful for this purpose in view oftheir ease of incorporation and ready means of detection.

Pharmaceutically acceptable solvates of the compounds disclosed hereinare contemplated. A solvate can be generated, e.g., by substituting asolvent used to crystallize a compound disclosed herein with an isotopicvariation (e.g., D₂O in place of H₂O, d₆-acetone in place of acetone, ord₆-DMSO in place of DMSO).

Pharmaceutically acceptable fluorinated variations of the compoundsdisclosed herein are contemplated and can be synthesized usingconventional methods known in the art or methods corresponding to thosedescribed in the Examples (substituting appropriate reagents withappropriate fluorinated variations of those reagents). Specifically, afluorinated variation is a compound in which at least one hydrogen atomis replaced by a fluoro atom. Fluorinated variations can providetherapeutic advantages resulting from greater metabolic stability, e.g.,increased in vivo half-life or reduced dosage requirements.

Pharmaceutically acceptable prodrugs of the compounds disclosed hereinare contemplated and can be synthesized using conventional methods knownin the art or methods corresponding to those described in the Examples(e.g., converting hydroxyl groups or carboxylic acid groups to estergroups). As used herein, a “prodrug” refers to a compound that can beconverted via some chemical or physiological process (e.g., enzymaticprocesses and metabolic hydrolysis) to a therapeutic agent. Thus, theterm “prodrug” also refers to a precursor of a biologically activecompound that is pharmaceutically acceptable. A prodrug may be inactivewhen administered to a subject, i.e. an ester, but is converted in vivoto an active compound, for example, by hydrolysis to the free carboxylicacid or free hydroxyl. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in an organism. Theterm “prodrug” is also meant to include any covalently bonded carriers,which release the active compound in vivo when such prodrug isadministered to a subject. Prodrugs of an active compound may beprepared by modifying functional groups present in the active compoundin such a way that the modifications are cleaved, either in routinemanipulation or in vivo, to the parent active compound. Prodrugs includecompounds wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the active compound is administered to asubject, cleaves to form a free hydroxy, free amino or free mercaptogroup, respectively. Examples of prodrugs include, but are not limitedto, acetate, formate and benzoate derivatives of an alcohol oracetamide, formamide and benzamide derivatives of an amine functionalgroup in the active compound and the like.

Characterization of Exemplary Bivalent Compounds

Specific exemplary bivalent compounds were characterized in KM12 cells.KM12 cells that express TPM3-TRKA fusion protein were treated with 100nM entrectinib (Entrec) or the bivalent compounds disclosed herein(CPD-001-CPD-065) for 16 hours. Cells were collected, lysed and subjectto immunoblotting using an antibody specific to TRK proteins. GAPDH wasincluded as the loading control. DMSO was used as the negative control.Following a 16-hour treatment of various bivalent compounds at 100 nM,TPM3-TRKA levels in KM12 cells were significantly decreased (FIGS.1A-1C).

Bi-functional compounds, exemplified by CPD-027, CPD-053, and CPD-060,were found to be partiucalrly effective in reducing TPM3-TRKA proteinlevels in KM12 cells (FIGS. 1A-1C). Treated with 100 nM CPD-027,CPD-053, or CPD-060 for various time points, significant degradation ofTPM3-TRKA in KM12 cells was readily detected 15 minutes after adding thebivalent compounds (FIG. 2). Additionally, a panel of selected compoundsdemonstrated the ability to induce significant degradation of TPM3-TRKAat concentration below 10 nM (FIGS. 5, 6 and 13). In addition toTPM3-TRKA, other TRK fusion proteins, such as AGBL4-TRKB and ETV6-TRKC,were also subject to bispecific compound-induced degradation (FIG. 7).The interaction with cereblon is critical to the ability of bispecificcompounds to induce degradation of TRK proteins, as a chemicalmodification that disrupted cereblon binding abolished TRKA degradationinduced by TR-123 (FIG. 8). The degradation was also dependent on theubiquitin-proteasome system, because it could be neutralized byco-administration of proteasome inhibitors, MG-132 and bortezomib, acullin E3 ligase inhibitor, MLN4924, or high concentration ofpomalidomide that compete for cereblon binding (FIG. 9). These findingscollectively demonstrate that bispecific compounds induce degradation ofTRK family proteins via a mechanism specifically mediated by cereblon,coffin E3 ligases, and the proteasome.

In addition to cultured cells, athymic nude mice bearing KM12subcutaneous xenograft tumors at the right flank were intraperitoneallytreated with 10, 20, or 50 mg/kg CPD-053, CPD-027, or CPD-060. Fourhours after drug administration, animals were sacrificed forimmunoblotting of TPM3-TPKA in homogenized xenograft tumor masses. Thelabel “a” or “b” represents two different samples of the same xenografttumor. Bivalent compounds, CPD-027, CPD-053, and CPD-060, exhibited theability of significantly reducing TPM3-TRKA protein levels in KM12subcutaneous xenograft tumors within 4 hours after a single dose of drugadministration (FIG. 3). Additional compounds, as exemplified by TR-123,TR-171, TR-172, TR-173, TR-177, and TR-181, also exhibited theactivities to induce TPM3-TRKA degradation in KM12 subcutaneous tumorsthrough intraperitoneal or oral administration (FIG. 10).

To investigate the pharmacokinetics of bi-functional compounds,exemplified by TR-123, a single 20 mg/kg intraperitoneal injection wasevaluated. Plasma concentration of TR-123 reported at each time pointrepresents the mean value derived from 3 experimental animals. Our datashowed significant plasma exposure of TR-123 over 12 hours (FIG. 11).Additionally, doses of 2 mg/kg TR-198 via intravenous injection and 20mg/kg TR-198 via oral gavage were evaluated in mice. Data showed thatthe oral bioavailability of TR-198 in mice was approximiately 16% (FIG.14).

The kinase activity of TRK is known to play important roles in tumorsexpressing TRK-fusion proteins, as TRK kinase inhibitors compromise cellproliferation, survival, and induce marked clinical responses (Amato etal., 2016; Drilon et al., 2018; Drilon et al., 2017; Khotskaya et al.,2017). KM12 cells seeded in 96-well plates were treated with 500 nMentrectinib or bivalent compounds, i.e. CPD-010, CPD-053, and CPD-057following a 12-point 2-fold serial dilution. Three days after treatment,cell viability was determined using the CellTiter-Glo kit followingmanufacturer's instructions. Cell viability was normalized to the meanvalues of 3 replicates of untreated cells. Dose-dependent response wasanalyzed following the least-squares non-linear regression method usingthe GraphPad Prism 5.0 software. Each data point in the figurerepresents the mean values of three technical replicates±standarddeviation. Bivalent compounds also dose-dependently suppressed viabilityof TPM3-TRKA-expressing KM12 cells, as exemplified by CPD-010, CPD-053,and CPD-057 (FIG. 4A). More specifically, all bivalent compounds thathad IC₅₀ values smaller than 1000 nM in KM12 cells induced degradationof TPM3-TRKA (FIG. 1 and Table 2-4). In contrast, when KM12 or H358cells were treated with 1000 nM CPD-053 following an 8-point 3-foldserial dilution, bivalent compounds, as exemplified by CPD-053, did notaffect cell viability in KRAS-mutant H358 cells (FIG. 4B). Finally,administration of bivalent compounds, as exemplified by CPD-060, TR-181,and TR-198, significantly repressed the growth of KM12 subcutaneousxenograft tumors without inducing substantial weight losses (FIGS. 12and 15). Take together, these results indicate that bivalent compoundsimpair KM12 cell proliferation, survival and tumorigenic potentialthrough specifically inducing degradation of TPM3-TRKA.

NGF and its primary receptor TRKA have been well recognized for theirroles in pain sensory (Denk et al., 2017). Targeting TRKA represents apromising therapeutic strategy for chronic pain management. Bivalentcompounds, exemplified by TR-123, have demonstrated the ability toinduce significant degradation of full-length TRKA, same as TPM3-TRKAfusion (FIGS. 8, and 9). The analgesic activities of bivalent compoundswere assessed using a widely used chronic pain model associated withosteoarthritis. Osteoarthritis was induced in the right knee of adultmale rats or guinea pigs following monoiodoacetate injection. One weeklater, animals were treated with TR-181 with ibuprofen as the positivecontrol. The pain sensory was assessed as weight distribution betweenthe injured limb and the contralateral limb using an incapacitancemeter. Data showed significant analgesic activity of TR-181 in theosteoarthritis models of rats and guinea pigs (FIG. 16).

Definition of Terms

As used herein, the terms “comprising” and “including” are used in theiropen, non-limiting sense.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation. An alkyl may comprise one, two, three, four, five, six,seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, orsixteen carbon atoms. In certain embodiments, an alkyl comprises one tofifteen carbon atoms (C₁-C₁₅ alkyl). In certain embodiments, an alkylcomprises one to thirteen carbon atoms (e.g., C₁-C₁₃ alkyl). In certainembodiments, an alkyl comprises one to eight carbon atoms (e. g., C₁-C₈alkyl). In other embodiments, an alkyl comprises five to fifteen carbonatoms (e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprisesfive to eight carbon atoms (e.g., C₅-C₈ alkyl). The alkyl is attached tothe rest of the molecule by a single bond, for example, methyl (Me),ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), pentyl, 3-methylhexyl, 2-methythexyl, andthe like.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond. An alkenyl may comprise two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,fifteen, or sixteen carbon atoms. In certain embodiments, an alkenylcomprises two to twelve carbon atoms (e.g., C₂-C₁₂ alkenyl). In certainembodiments, an alkenyl comprises two to eight carbon atoms (e.g., C₂-C₈alkenyl). In certain embodiments, an alkenyl comprises two to six carbonatoms (e.g., C₂-C₆ alkenyl). In other embodiments, an alkenyl comprisestwo to four carbon atoms (e.g., C₂-C₄ alkenyl). The alkenyl is attachedto the rest of the molecule by a single bond, for example, ethenyl(i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl,penta-1,4-dienyl, and the like.

The term “allyl,” as used herein, means a —CH₂CH═CH₂ group.

As used herein, the term “alkynyl” refers to a straight or branchedhydrocarbon chain radical group consisting, solely of carbon andhydrogen atoms, containing at least one triple bond. An alkynyl maycomprise two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In certainembodiments, an alkynyl comprises two to twelve carbon atoms (e.g.,C₂-C₁₂ alkynyl). In certain embodiments, an alkynyl comprises two toeight carbon atoms (e.g., C₂-C₈ alkynyl). In other embodiments, analkynyl has two to six carbon atoms (e.g., C₂-C₆ alkynyl). In otherembodiments, an alkynyl has two to four carbon atoms (e.g., C₂-C₄alkynyl). The alkynyl is attached to the rest of the molecule by asingle bond. Examples of such groups include, but are not limited to,ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, and the like.

The term “alkoxy”, as used herein, means an alkyl group as definedherein witch is attached to the rest of the molecule via an oxygen atom.Examples of such groups include, but are not limited to, methoxy,ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, iso-butoxy, tert-butoxy,pentyloxy, hexyloxy, and the like.

The term “aryl”, as used herein, “refers to a radical derived from anaromatic monocyclic or multicyclic hydrocarbon ring system by removing ahydrogen atom from a ring carbon atom. The aromatic monocyclic ormulticyclic hydrocarbon ring system contains only hydrogen and carbonatoms. An aryl may comprise from six to eighteen carbon atoms, where atleast one of the rings in the ring system is fully unsaturated, i.e., itcontains a cyclic, delocalized (4n+2) π-electron system in accordancewith the Hückel theory. In certain embodiments, an aryl comprises six tofourteen carbon atoms (C₆-C₁₄ aryl). In certain embodiments, an arylcomprises six to ten carbon atoms (C₆-C₁₀ aryl). Examples of such groupsinclude, but are not limited to, phenyl, fluorenyl and naphthyl. Theterms “Ph” and “phenyl,” as used herein, mean a —C₆H₅ group.

The term “heteroaryl”, refers to a radical derived from a 3- to18-membered aromatic ring radical that comprises two to seventeen carbonatoms and from one to six heteroatoms selected from nitrogen, oxygen andsulfur. As used herein, the heteroaryl radical may be a monocyclic,bicyclic, tricyclic or tetracyclic ring system, wherein at least one ofthe rings in the ring system is fully unsaturated, i.e., it contains acyclic, delocalized (4n+2) π-electron system in accordance with theHückel theory. Heteroaryl includes fused or bridged ring systems. Incertain embodiments, a heteroaryl refers to a radical derived from a 3-to 10-membered aromatic ring radical (3-10 membered heteroaryl). Incertain embodiments, a heteroaryl refers to a radical derived from 5- to7-membered aromatic ring (5-7 membered heteroaryl). Heteroaryl includesfused or bridged ring systems. The heteroatom(s) in the heteroarylradical is optionally oxidized. One or more nitrogen atoms, if present,are optionally quaternized. The heteroaryl is attached to the rest ofthe molecule through any atom of the ring(s). Examples of such groupsinclude, but not limited to, pyridinyl, imidazolyl, pyrimidinyl,pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl,thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinalinyl,indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and the like.In certain embodiments, an heteroaryl is attached to the rest of themolecule via a ring carbon atom. In certain embodiments, an heteroarylis attached to the rest of the molecule via a nitrogen atom (N-attached)or a carbon atom (C-attached). For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl(N-attached) or imidazol-3-yl (C-attached).

The term “heterocyclyl”, as used herein, means a non-aromatic,monocyclic, bicyclic, tricyclic, or tetracyclic radical having a totalof from 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 atoms in its ring system,and containing from 3 to 12 carbon atoms and from 1 to 4 heteroatomseach independently selected from O, S and N, and with the proviso thatthe ring of said group does not contain two adjacent O atoms or twoadjacent S atoms. A heterocyclyl group may include fused, bridged orspirocyclic ring systems. In certain embodiments, a hetercyclyl groupcomprises 3 to 10 ring atoms (3-10 membered heterocyclyl). In certainembodiments, a hetercyclyl group comprises 3 to 8 ring atoms (3-8membered heterocyclyl). In certain embodiments, a hetercyclyl groupcomprises 4 to 8 ring atoms (4-8 membered heterocyclyl). In certainembodiments, a hetercyclyl group comprises 3 to 6 ring atoms (3-6membered heterocyclyl). A heterocyclyl group may contain an oxosubstituent at any available atom that will result in a stable compound.For example, such a group may contain an oxo atom at an available carbonor nitrogen atom. Such a group may contain more than one oxo substituentif chemically feasible. In addition, it is to be understood that whensuch a heterocyclyl group contains a sulfur atom, said sulfur atom maybe oxidized with one or two oxygen atoms to afford either a sulfoxide orsulfone. An example of a 4 membered heterocyclyl group is azetidinyl(derived from antidine). An example of a 5 membered cycloheteroalkylgroup is pyrrolidinyl. An example of a 6 membered cycloheteroalkyl groupis piperidinyl. An example of a 9 membered cycloheteroalkyl group isindolinyl. An example of a 10 membered cycloheteroalkyl group is4H-quinolizinyl. Further examples of such heterocyclyl groups include,but are not limited to, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, molpholino, thiomorphohno, thioxanyl,piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl,thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,2H-pyran 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, quinolizinyl, 3-oxopiperazinyl,4-methylpiperazinyl, 4-ethylpiperazinyl, and1-oxo-2,8,diazaspiro[4.5]dec-8-yl. A heteroaryl group may be attached tothe rest of molecular via a carbon atom (C-attached) or a nitrogen atom(N-attached). For instance, a group derived from piperazine may bepiperazin-1-yl (N-attached) or piperazin-2-yl (C-attached).

The term “ cycloalkyl” means a saturated, monocyclic, bicyclic,tricyclic, or tetracyclic radical having a total of from 4, 5, 6, 7, 8,9, 10, 11, 12, or 13 carbon atoms in its ring system. A cycloalkyl maybe fused, bridged or spirocyclic. In certain embodiments, a cycloalkylcomprises 3 to 8 carbon ring atoms (C₃-C₈ cycloalkyl). In certainembodiments, a cycloalkyl comprises 3 to 6 carbon ring atoms C₃-C₆cycloalkyl). Examples of such groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cycloheptyl, adamantyl, and the like.

The term “cycloalkylene” is a bidentate radical obtained by removing ahydrogen atom from a cycloalkyl ring as defined above. Examples of suchgroups include, but are not limited to, cyclopropylene, cyclobutylene,cyclopentylene, cyclopentenylene, cyclohexylene, cycloheptylene, and thelike.

The term “spirocyclic” as used herein has its conventional meaning, thatis, any ring system containing two or more rings wherein two of therings have one ring carbon in common. Each ring of the spirocyclic ringsystem, as herein defined, independently comprises 3 to 20 ring atoms.Preferably, they have 3 to 10 ring atoms. Non-limiting examples of aspirocyclic system include spiro[3.3]heptane, spiro[3.4]octane, andspiro[4.5]decane.

The term cyano” refers to a —C≡N group.

An “aldehyde” group refers to a —C(O)H group.

An “alkoxy” group refers to both an —O-alkyl, as defined herein.

An “alkoxycarbonyl” refers to a —C(O)-alkoxy, as defined herein.

An “alkylaminoalkyl” group refers to an -alkyl-NR-alkyl group, asdefined herein.

An “alkylsulfonyl” group refers to a —SO₂alkyl, as defined herein.

An “amino” group refers to an optionally substituted —NH₂.

An “aminoalkyl” group refers to an -alky-amino group, as defined herein.

An “aminocarbonyl” refers to a —C(O)-amino, as defined herein.

An “arylalkyl” group refers to -alkylaryl, where alkyl and aryl aredefined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

An “aryloxycarbanyl” refers to —C(O)-aryloxy, as defined herein.

An “arylsulfonyl” group refers to a —SO₂aryl, as defined herein.

A “carbonyl” group refers to a —C(O)-group, as defined herein.

A “carboxylic acid” group refers to a —C(O)OH group.

A “cycloalkoxy” refers to a —O-cycloalkyl group, as defined herein.

A “halo” or “halogen” group refers to fluorine, chlorine, bromine oriodine.

A “haloalkyl” group refers to an alkyl group substituted with one ormore halogen atoms.

A “hydroxy” group refers to an —OH group.

A “nitro” group refers to a —NO₂ group.

An “oxo” group refers to the ═O substituent.

A “trihalomethyl” group refers to a methyl substituted with threehalogen atoms.

The term “substituted,” means that the specified group or moiety bearsone or more substituents independently selected from C₁-C₄ alkyl, aryl,heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl,—OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl,halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl),—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄alkylphenyl), cyano, nitro, oxo, —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “null” means the absence of an atom or moiety, and there is abond between adjacent atoms in the structure.

The term “optionally substituted” means that the specified group may beeither unsubstituted or substituted by one or more substituents asdefined herein. It is to be understood that in the compounds of thepresent invention when a group is said to be “unsubstituted,” or is“substituted” with fewer groups than would fill the valencies of all theatoms in the compound, the remaining valencies on such a group arefilled by hydrogen. For example, if a C₆ aryl group, also called“phenyl” herein, is substituted with one additional substituent, one ofordinary skill in the art would understand that such a group has 4 openpositions left on carbon atoms of the C₆ aryl ring (6 initial positions,minus one at which the remainder of the compound of the presentinvention is attached to and an additional substituent, remaining 4positions open). In such cases, the remaining 4 carbon atoms are eachbound to one hydrogen atom to fill their valencies. Similarly, if a C₆aryl group in the present compounds is said to be “disubstituted ” oneof ordinary skill in the art would understand it to mean that the C₆aryl has 3 carbon atoms remaining that are unsubstituted. Those threeunsubstituted carbon atoms are each bound to one hydrogen atom to filltheir valencies.

As used herein, the same symbol in different FORMULA means differentdefinition, for example, the definition of R1 in FORMULA 1 is as definedwith respect to FORMULA 1 and the definition of R1 in FORMULA 6 is asdefined with respect to FORMULA 6.

As used herein, when m (or n or o or p) is definited by a range, forexample, “m is 0 to 15” or “m=0-3” mean that in is an integer from 0 to15 (i.e. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15)or m is an integer from 0 to 3(i.e. m is 0, 1,2, or 3) or is any integerin the defined range.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the bivalentcompounds described herein is intended to encompass any and allpharmaceutically suitable salt forms. Preferred pharmaceuticallyacceptable salts of the compounds described herein are pharmaceuticallyacceptable acid addition salts and pharmaceutically acceptable baseaddition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic acid, aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfortic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumaratcs, maleates,mandelates, benzoates, chloroberizoates, methylbenzoates,dinitrobenzoates, phthalates, benzensulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexanple, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997), which is hereby incorporated byreference in its entirety). Acid addition salts of basic compounds maybe prepared by contacting the flee base forms with a sufficient amountof the desired acid to produce the salt according to methods andtechniques with which a skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are, not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but amnot limited. to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethlaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenethylenediamine, chloroprocaine, hydrabamine, choline, betaine,ethylenediamine, ethylenediartiline, N-methylglucamine, glucosamine,metylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. See Berge et al.,supra.

Pharmaceutical Compositions

In some aspects, the compositions and methods described herein includethe manufacture and use of pharmaceutical compositions and medicamentsthat include one or more bivalent compounds as disclosed herein. Alsoincluded are the pharmaceutical compositions themselves.

In some aspects, the compositions disclosed herein can include othercompounds, drugs, or agents used for the treatment of cancer. Forexample, in some instances, pharmaceutical compositions disclosed hereincan be combined with One or more (e.g., one, two, three, four, five, orless than ten) compounds. Such additional compounds can include, e.g.,conventional chemotherapeutic agents or any other cancer treatment knownin the art. When co-administered, bivalent compounds disclosed hereincan operate in conjunction with conventional chemotherapeutic agents orany other cancer treatment known in the art to produce mechanisticallyadditive or synergistic therapeutic effects.

In some aspects, the pH of the compositions disclosed herein can beadjusted with pharmaceutically acceptable acids, bases, or buffers toenhance the stability of the bivalent compound or its delivery form.

Pharmaceutical compositions typically include a pharmaceuticallyacceptable excipient, adjuvant, or vehicle. As used herein, the phrase“pharmaceutically acceptable” refers to molecular entities andcompositions that are generally believed to be physiologically tolerableand do not typically produce an allergic or similar untoward reaction,such as gastric upset, dizziness and the like, when administered to ahuman. A pharmaceutically acceptable excipient, adjuvant, or vehicle isa substance that can be administered to a patient, together with acompound of the invention, and which does not compromise thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.Exemplary conventional nontoxic pharmaceutically acceptable excipients,adjuvants, and vehicles include, but not limited to, saline, solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents, and the like, compatible withpharmaceutical administration.

In particular, pharmaceutically acceptable excipients, adjuvants, andvehicles that can be used in the pharmaceutical compositions of thisinvention include, but are, not limited to, ion exchangers, alumina,aluminum stearate, lecithin, self-emulsifying drug delivery systems(SEDDs) such as d-α-tocopherol polyethylene glycol 1000 succinate,surfactants used in pharmaceutical dosage forms such as Tweens or othersimilar polymeric delivery matrices, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, may also beadvantageously used to enhance delivery of compounds of the formulaedescribed herein.

Depending on the dosage form selected to deliver the bivalent compoundsdisclosed herein, different pharmaceutically acceptable excipients,adjuvants, and vehicles may be used. In the case of tablets for oraluse, pharmaceutically acceptable excipients, adjuvants, and vehicles maybe used include lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. For oral administration ina capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions or emulsions are administered orally, theactive ingredient may be suspended or dissolved in an oily phase iscombined with emulsifying or suspending agents. If desired, certainsweetening, flavoring, or coloring agents can be added.

As used herein, the, bivalent compounds disclosed herein are defined toinclude pharmaceutically acceptable derivatives or prodrugs thereof. A“pharmaceutically acceptable derivative” means any pharmaceuticallyacceptable salt, solvate, or prodrug, e.g., carbamate, ester, phosphateester, salt of an ester, or other derivative of a compound or agentdisclosed herein, which upon administration to a recipient is capable ofproviding (directly or indirectly) a compound described herein, or anactive metabolite or residue thereof. Particularly favored derivativesand prodrugs are those that increase the bioavailability of thecompounds disclosed herein when such compounds are administered to asubject (e.g., by allowing an orally administered compound to be morereadily absorbed into the blood) or which enhance delivery of the parentcompound to a biological compartment (e.g., the brain or lymphaticsystem) relative to the parent species. Preferred prodrugs includederivatives where a group that enhances aqueous solubility or activetransport through the gut membrane is appended to the structure offormulae described herein. Such derivatives are recognizable to thoseskilled in the art without undue experimentation. Nevertheless,reference is made to the teaching of Burger's Medicinal Chemistry andDrug Discovery, 5^(th) Edition, Vol. 1: Principles and Practice, whichis incorporated herein by reference to the extent of teaching suchderivatives.

The bivalent compounds disclosed herein include pure enantiomers,mixtures of enantiomers, pure diastereoisomers, mixtures ofdiastereoisomers, diastereoisomeric racemates, mixtures ofdiastereoisomeric racemates and the meso-form and pharmaceuticallyacceptable salts, solvent complexes, morphological forms, or deuteratedderivatives thereof.

In some aspects, the pharmaceutical compositions disclosed herein caninclude an effective amount of one or more bivalent compounds. The terms“effective amount” and “effective to treat,” as used herein, refer to anamount or a concentration of one or more compounds or a pharmaceuticalcomposition described herein utilized for a period of time (includingacute or chronic administration and periodic or continuousadministration) that is effective within the context of itsadministration for causing an intended effect or physiological outcome(e.g., treatment or prevention of cell growth, cell proliferation, orcancer). In some aspects, pharmaceutical compositions can furtherinclude one or more additional compounds, drugs, or agents used for thetreatment of cancer (e.g., conventional chemotherapeutic agents) inamounts effective for causing an intended effect or physiologicaloutcome (e,g., treatment or prevention of cell growth, cellproliferation, or cancer).

In some aspects, the pharmaceutical compositions disclosed herein can beformulated for sale in the United States, import into the United States,or export from the United States.

Administration of Pharmaceutical Compositions

The pharmaceutical compositions disclosed herein can be formulated oradapted for administration to a subject via any route, e.g., any routeapproved by the Food and Drug Administration (FDA). Exemplary methodsare described in the FDA Data Standards Manual (DSM) (available athttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/DataStandardsManualmonographs).In particular, the pharmaceutical compositions can be formulated for andadministered via oral, parenteral, or transdermal delivery. The term“parenteral” as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intraperitoneal, intra-articular,intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional,and intracranial injection or infusion techniques.

For example, the pharmaceutical compositions disclosed herein can beadministered, e.g., topically, rectally, nasally (e.g., by inhalationspray or nebulizer), buccally, vaginally, subdermally (e.g., byinjection or via an implanted reservoir), or ophthalmically.

For example, pharmaceutical compositions of this invention can be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions.

For example, the pharmaceutical compositions of this invention can beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax, and polyethyleneglycols.

For example, the pharmaceutical compositions of this invention can beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and can be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, or other solubilizing or dispersingagents known in the art.

For example, the pharmaceutical compositions of this invention can beadministered by injection (e.g., as a solution or powder). Suchcompositions can be formulated according to techniques known in the artusing suitable dispersing or wetting agents (such as, for example, Tween80) and suspending agents. The sterile injectable preparation may alsobe a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, e.g., as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are mannitol, water, Ringer's solution, and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil can be employed, including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, e.g., olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions can also contain a long-chain alcohol diluent or dispersant,or carboxymethyl cellulose or similar dispersing agents which arecommonly used in the formulation of pharmaceutically acceptable dosageforms such as emulsions and or suspensions. Other commonly usedsurfactants such as Tweens, Spans, or other similar emulsifying agentsor bioavailability enhancers which are commonly used in the manufactureof pharmaceutically acceptable solid, liquid, or other dosage forms canalso be used for the purposes of formulation.

In some aspects, an effective dose of a pharmaceutical composition ofthis invention can include, but is not limited to, e.g., about 0.00001,0.0001, 0.001, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09,0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7,0.75, 0,8, 0.85, 0.9, 0.95, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7,8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500,600, 700, 800, 900, 1000, 2500, 5000, or 10000 mg/kg/day, or accordingto the requirements of the particular pharmaceutical composition.

When the pharmaceutical compositions disclosed herein include acombination of the bivalent compounds described herein and one or moreadditional compounds (e.g., one or more additional compounds, drugs, oragents used for the treatment of cancer or any other condition ordisease, including conditions or diseases known to be associated with orcaused by cancer), both the bivalent compounds and the additionalcompounds may be present at dosage levels of between about 1 to 100%,and more preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents can beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents can be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

In some aspects, the pharmaceutical compositions disclosed herein can beincluded in a container, pack, or dispenser together with instructionsfor administration.

Methods of Treatment

The methods disclosed herein contemplate administration of an effectiveamount of a compound or composition to achieve the desired or statedeffect. Typically, the compounds or compositions of the invention willbe administered from about 1 to about 6 times per day or, alternately orin addition, as a continuous infusion. Such administration can be usedas a chronic or acute therapy. The amount of active ingredient that canbe combined with the carrier materials to produce a single dosage formwill vary depending upon the host treated and the particular mode ofadministration. A typical preparation will contain from about 5% toabout 95% active compound (w/w). Alternatively, such preparations cancontain from about 20% to about 80% active compound.

In some aspects, provided herein are a bivalent compound describedherein for preventing or treating a disease or condition.

In some aspects, provided herein are a bivalent compound describedherein for treating or preventing one or more diseases or conditionsdisclosed herein in a subject in need thereof. In certain embodiments,the disease or condition is a TRK-mediated disease or condition. Incertain embodiments, the disease or condition is resulted from TRKexpression, mutation, or fusion. In certain embodiments, the disease orcondition comprises non-small cell lung cancer, colorectal cancer,gastric cancer, liver cancer, invasive breast cancer, lungadenocarcinoma, uterine cancer, adrenal cancer, pancreatic cancer,ovarian cancer, esophageal cancer, urinary bladder cancer, endometrialcancer, prostate cancer low-grade glioma, glioblastoma, Spitzoid cancer,soft tissue sarcoma, papillary thyroid carcinoma, head and neck squamouscell carcinoma, congenital fibrosarcoma, congenital mesoblasticnephroma, secretory breast carcinoma, mammary analogue secretorycarcinoma, acute myeloid leukemia, ductal carcinoma, pulmonaryneuroendocrine tumors, pheochromocytoma, and Wilms' tumor. In certainembodiments, the disease or condition comprises cancer, inflammatorydiseases, acute and chronic pain, pruritus, bone-related diseases,neurodegenerative diseases, infectious diseases, and other diseases,including but not limited to neuroblastoma, prostate cancer, pancreaticcancer, melanoma, head and neck cancer, gastric carcinoma, lungcarcinoma, liver cancer, uterine cancer, adrenal cancer, biliary treecancer, intestinal cancer, colorectal cancer, ovarian cancer, lungcarcinoma, small cell lung cancer, non-small cell lung cancer, gastriccarcinoma, breast cancer, esophageal cancer, urinary bladder cancer,endometrial cancer, brain cancer, low-grade glioma, glioblastoma,medulloblastoma, secratory breast cancer, secretory breast carcinoma,salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma,adult myeloid leukemia, acute myeloid leukemia, large cellneuroendocrine tumors, pulmonary neuroendocrine tumors, sarcomas,pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenitalmesoblastic nephroma, secretory breast carcinoma, malignant fibroushistiocytoma, embryonal rhabdoinysocarcoma, leionlysosarcoma,neuro-fibrosarcoma, neoplasms of the central nervous systems,osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma,Spitzoid cancer, Wilms' tumor, lymphomas (e.g. including Hodgkin'slymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma,mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma,B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplasticlarge cell lymphoma), inflammatory lung diseases (e.g. asthma),inflammatory bowel diseases, (e.g. ulcerative colitis, Crohn's disease),inflammatory skin diseases (e.g. atopic dermatitis, eczema andpsoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain,cancer pain, surgical pain, inflammatory pain, neuropathic pain,nociceptive pain, pain of osteoarthritis, chronic low back pain, lowback pain of osteoporosis, pain of bone fracture, pain of rheumatoidarthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia,pain of pancreatitis, pain of interstitial cystitis, pain ofendometriosis, pain of irritable bowel syndrome, migraine, pain ofpulpitis, interstitial cystitis pain, painful bladder syndrome, centralpain syndromes, postsurgical pain syndromes, bone and joint pain,repetitive motion pain, dental pain, myofascial pain, perioperativepain, dysmennorhea, myofascial pain, angina pain, headache, primaryhyperalgesia, secondary hyperalgesia, primary allodynia, secondaryallodynia, other pain caused by central sensitization, systemiccutaneous pruritus, localized cutaneous pruritus, senile cutaneouspruritus, gestational pruritus, pruritus ani, vulvar pruritus,metastatic bone disease, treatment-induce bone loss, osteoporosis,rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget'sdisease, periodontal disease, osteolytic disease, multiple sclerosis,Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia,anorexia, demyelination and dysmyelination. In certain embodiments, thedisease or condition is a relapsed disease. In certain embodiments, thedisease or condition is a relapsed cancer, in certain embodiments, thedisease or condition is refractory to one or more previous treatments.

In some aspects, provided herein are use of a bivalent compound inmanufacture of a medicament for preventing or treating one or morediseases or conditions disclosed herein.

In some aspects, the methods disclosed include the administration of atherapeutically effective amount of one or more of the compounds orcompositions described herein to a subject (e.g., a mammalian subject,e.g., a human subject) who is in need of, or who has been determined tobe in need of, such treatment. In some aspects, the methods disclosedinclude selecting a subject and administering to the subject aneffective amount of one or more of the compounds or compositionsdescribed herein, and optionally repeating administration as requiredfor the prevention or treatment of cancer.

In some aspects, subject selection can include obtaining a sample from asubject (e.g., a candidate subject) and testing the sample for anindication that the subject is suitable for selection. In some aspects,the subject can be confirmed or identified, e.g. by a health careprofessional, as having had, having an elevated risk to have, or havinga condition or disease. In some aspects, suitable subjects include, forexample, subjects who have or had a condition or disease but thatresolved the disease or an aspect thereof, present reduced symptoms ofdisease (e.g., relative to other subjects (e.g., the majority ofsubjects) with the same condition or disease), or that survive forextended periods of time with the condition or disease (e.g., relativeto other subjects (e.g., the majority of subjects) with the samecondition or disease), e.g., in an asymptomatic state (e.g., relative toother subjects (e.g., the majority of subjects) with the same conditionor disease). In some aspects, exhibition of a positive immune responsetowards a condition or disease can be made from patient records, familyhistory, or detecting an indication of a positive immune response. Insome aspects, multiple parties can be included in subject selection. Forexample, a first party can obtain a sample from a candidate subject anda second party can test the sample. In some aspects, subjects can beselected or referred by a medical practitioner (e.g., a generalpractitioner). In some aspects, subject selection can include obtaininga sample from a selected subject and storing the sample or using the inthe methods disclosed herein. Samples can include, e.g., cells orpopulations of cells.

In some aspects, methods of treatment can include a singleadministration, multiple administrations, and repeating administrationof one or more compounds disclosed herein as required for the preventionor treatment of the disease or condition disclosed herein (e.g., anTRK-mediated disease). In some aspects, methods of treatment can includeassessing a level of disease in the subject prior to treatment, duringtreatment, or after treatment. In some aspects, treatment can continueuntil a decrease in the level of disease in the subject is detected.

The term “subject,” as used herein, refers to any animal. In someinstances, the subject is a mammal. In some instances, the term“subject,” as used herein, refers to a human (e.g., a man, a woman, or achild).

The terms “administer,” “administering,” or “administration,” as usedherein, refer to implanting, ingesting, injecting, inhaling, orotherwise absorbing a compound or composition, regardless of form. Forexample, the methods disclosed herein include administration of aneffective amount of a compound or composition to achieve the desired orstated effect.

The terms “treat”, “treating,” or “treatment,” as used herein, refer topartially or completely alleviating, inhibiting, ameliorating, orrelieving the disease or condition from which the subject is suffering.This means any manner in which one or more of the symptoms of a diseaseor disorder (e.g., cancer) are ameliorated or otherwise beneficiallyaltered. As used herein, amelioration of the symptoms of a particulardisorder (e.g., cancer) refers to any lessening, whether permanent ortemporary, lasting or transient that can be attributed to or associatedwith treatment by the bivalent compounds, compositions and methods ofthe present invention. In some embodiments, treatment can promote orresult in, for example, a decrease in the number of tumor cells (e.g.,in a subject) relative to the number of tumor cells prior to treatment;a decrease in the viability (e.g., the average/mean viability) of tumorcells (e.g., in a subject) relative to the viability of tumor cellsprior to treatment; a decrease in the rate of growth of tumor cells; adecrease in the rate of local or distant tumor metastasis; or reductionsin one or more symptoms associated with one or more tumors in a subjectrelative to the subject's symptoms prior to treatment.

The terms “prevent,” “preventing,” and “prevention,” as used herein,shall refer to a decrease in the occurrence of a disease or decrease inthe risk of acquiring a disease or its associated symptoms in a subject.The prevention may be complete, e.g., the total absence of disease orpathological cells in a subject. The prevention may also be partial,such that the occurrence of the disease or pathological cells in asubject is less than, occurs later than, or develops more slowly thanthat which would have occurred without the present invention. In certainembodiments, the subject has an elevated risk of developing one or moreTRK-mediated diseases. Exemplary TRK-mediated diseases that can betreated with bivalent compounds include, for example, non-small celllung cancer, colorectal cancer, gastric cancer, liver cancer, invasivebreast cancer, lung adenocarcinoma, uterine cancer, adrenal cancer,pancreatic cancer, ovarian cancer, esophageal cancer, urinary bladdercancer, endometrial cancer, prostate cancer low-grade glioma,glioblastoma, spitzoid cancer, soft tissue sarcoma, papillary thyroidcarcinoma, head and neck squamous cell carcinoma, congenitalfibrosarcoma, congenital mesoblastic nephroma, secretory breastcarcinoma, mammary analogue secretory carcinoma, acute myeloid leukemia,ductal carcinoma, pulmonary neuroendocrine tumors, pheochromocytoma, andWilms' tumor. Exemplary TRK-mediated diseases that can be treated withbivalent compounds include, for example, cancer, inflammatory diseases,acute and chronic pain, pruritus, bone-related diseases,neurodegenerative diseases, infectious diseases, and other diseases,including but not limited to neuroblastoma, prostate cancer, pancreaticcancer, melanoma, head and neck cancer, gastric carcinoma, lungcarcinoma, liver cancer, uterine cancer, adrenal cancer, biliary treecancer, intestinal cancer, colorectal cancer, ovarian cancer, lungcarcinoma, small cell lung cancer, non-small cell lung cancer, gastriccarcinoma, breast cancer, esophageal cancer, urinary bladder cancer,endometrial cancer, brain cancer, low-tirade glioma, glioblastoma,medulloblastoma, secretory breast cancer, secretory breast carcinoma,salivary gland cancer, papillary thyroid carcinoma, ductal carcinoma,adult myeloid leukemia, acute myeloid leukemia, large cellneuroendocrine tumors, pulmonary neuroendocrine tumors, sarcomas,pheochromocytoma, fibrosarcoma, congenital fibrosarcoma, congenitalmesoblastic nephroma, secretory breast carcinoma, malignant fibroushistiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma,neuro-fibrosarcoma, neoplasms of the central nervous systems,osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma,Spitzoid cancer, Wilms' tumor, lymphomas (e.g. including Hodgkin'slymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma,mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma,B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplasticlarge cell lymphoma), inflammatory lung diseases (e.g. asthma),inflammatory bowel diseases, (e.g. ulcerative colitis Crohn's disease),inflammatory skin diseases (e.g. atopic dermantis, eczema andpsoriasis), interstitial cystitis, rhinitis, acute pain, chronic pain,cancer pain, surgical pain, inflammatory pain, neuropathic pain,nociceptive pain, pain of osteoarthritis, chronic low back pain, lowback pain of osteoporosis, pain of bone fracture, pain of rheumatoidarthritis, postherpetic pain, pain of diabetic neuropathy, fibromyalgia,pain of pancreatitis, pain of interstitial cystitis, pain ofendometriosis, pain of irritable bowel syndrome, migraine, pain ofpulpitis, interstitial cystitis pain, painful bladder syndrome, centralpain syndromes, postsurgical pain syndromes, bone and joint pain,repetitive motion pain, dental pain, myofascial pain, perioperativepain, dysmennorhea, myofascial pain, angina pain, headache, primaryhyperalgesia, secondary hyperalgesia, primary allodynia, secondaryallodynia, other pain caused by central sensitization, systemiccutaneous pruritus, localized cutaneous pruritus, senile cutaneouspruritus, gestational pruritus, pruritus ani, vulvar pruritus,metastatic bone disease, treatment-induce bone loss, osteoporosis,rheumatoid arthritis, bone metastases, ankylosing spondylitis, Paget'sdisease, periodontal disease, osteolytic disease, multiple sclerosis,Parkinson's disease, Alzheimer's disease, Chagas disease, cachexia,anorexia, demyelination and dysmyelination.

Specific dosage and treatment regimens for any particular patient willdepend upon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

An effective amount can be administered in one or more administrations,applications or dosages. A therapeutically effective amount of atherapeutic compound (i.e., an effective dosage) depends on thetherapeutic compounds selected. Moreover, treatment of a subject with atherapeutically effective amount of the compounds or compositionsdescribed herein can include a single treatment or a series oftreatments. For example, effective amounts can be administered at leastonce. The compositions can be administered from one or more times perday to one or more times per week; including once every other day. Theskilled artisan will appreciate that certain factors can influence thedosage and timing required to effectively treat a subject, including butnot limited to the severity of the disease or disorder, previoustreatments, the general health or age of the subject, and other diseasespresent.

Following administration, the subject can be evaluated to detect,assess, or determine their level of disease. In some instances,treatment can continue until a change (e.g., reduction) in the level ofdisease in the subject is detected. Upon improvement of a patient'scondition (e.g., a change (e.g., decrease) in the level of disease inthe subject), a maintenance dose of a compound, or composition disclosedherein can be administered, if necessary. Subsequently, the dosage orfrequency of administration, or both, can be reduced, e.g., as afunction of the symptoms, to a level at which the improved condition isretained. Patients may, however, require intermittent treatment on along-term basis upon any recurrence of disease symptoms.

The present disclosure is also described and demonstrated by way of thefollowing examples. However, the use of these and other examplesanywhere in the specification is illustrative only and in no way unfitsthe scope and meaning of the invention or of any exemplified term.Likewise, the invention is not limited to any particular preferredembodiment or aspect described herein. Indeed, many modifications andvariations may be apparent to those skilled in the art upon reading thisspecification, and such variations can be made without departing fromthe invention in spirit or in scope. The invention is therefore to belimited only by the terms of the appended claims along with the fullscope of equivalents to which those claims are entitled.

EXAMPLES Example 1:4-((2-Aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isodoline-1,3-dione(Linker 1)

A solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione(1.66 g, 6.0 mmol), tert-butyl (2-aminoethyl)carbamate (1.25 g, 6.6mmol) and N,N-diisopropylethylamine (2.32 g, 18 mmmol) in DMF (12 mL)was heated to 85° C. in a microwave reactor for 50 min. Three batcheswere combined and diluted with EtOAc (200 mL). The reaction was washedwith water and brine. The separated organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresulting residue was purified by silica gel chromatography (eluted withhexanes/EtOAc=1:1) to give tert-butyl(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin4-yl)amino)ethyl)carbamate(1.3 g, yield: 16%) as a yellow solid. MS (ESI) m/z 317.1 [M-100+H]⁺. Asolution of tert-butyl(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)carbamate (2.0 g, 4.5 mmol) in DCM (10 mL) and TFA (5 mL)was stirred at room temperature for 2 h. The reaction was concentratedand triturated with EtOAc. The solid precipitate was filtered. And thesolid was washed with MTBE, and dried to give4-((2-aminoethyl)amino)-2-(2,6-dioxopipeirdin-3-yl)isoindoline-1,3-dioneas a yellow solid (Linker 1) (1.3 g, yield: 98%). ¹H NMR (400 MHz,DMSO-d₆) δ 11.14 (s, 1H), 7.85 (s, 3H), 7.45 (t, J=7.2 Hz, 1H), 7.19 (d,J=7.2 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 6.84 (t, J=6.4 Hz, 1H), 5.07 (dd,J=5.2, 12.8 Hz, 1H), 3.58 (q, J=6.41 Hz, 2H), 3.00 (s, 2H), 2.94-2.85(m, 1H), 2.62-2.50 (m, 2H), 2.05-2.00 (m, 1H). MS (ESI) m/z=317.1[M+H]⁺.

Example 2:4-((3-Aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 2)

Linker 2 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (1.2 g, yield: 11% over 2 steps). ¹H NMR (400MHz, DMSO-d6) 11.11 (s, 1H), 7.74 (s, 3H), 7.62-7.58 (m, 1H), 7.15 (d,J=8.4 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.78-6.75 (m, 1H), 5.08-5.04 (m,1H), 3.43-3.36 (m, 2H), 2.90-2.86 (m, 3H), 2.62-2.51 (m, 2H), 2.08-2.01(m, 1H), 1.86-1.80 (m, 2H). MS (ESI) m/z=331.1 [M+H]⁺.

Example 3:4-((4-Aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 3)

Linker 3 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (1.4 g, yield: 15% over 2 steps). ¹H NMR (400MHz, DMSO-d6) 11.11(s, 1H), 7.84 (s, 3H), 7.62-7.57 (m, 1H), 7.13 (d,J=8.4 Hz, 1H), 7.04 (d, J=6.8 Hz, 1H), 6.62 (s, 1H), 5.08-5.04 (m, 1H),3.34 (s, 2H), 2.90-2.83 (m, 3H), 2.62-2.51 (m, 2H) 2.06-2.01 (m, 1H),1.65-1.60(m, 4H). MS (ESI) m/z=345.1 [M+H]+.

Example 4:4-((5-Aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 4)

Linker 4 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (2.3 g, yield: 26% over 2 steps). ¹H NMR (400MHz, DMSO-d₆) δ 11.14 (s, 1H), 7.72 (s, 3H), 7.61-7.57 (m, 1H), 7.10 (d,J=8.4 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 6.56-6.53 (m, 1H), 5.07-5.03 (m,1H), 3.32-3.28 (m, 2H), 2.90-2.78 (m, 3H), 2.62-2.51 (m, 2H), 2.05-1.90(m, 1H), 1.62-1.54 (m, 4H), 1.41-1.37 (m, 2H). MS (ESI) m/z=359.1[M+H]⁺.

Example 5:4-((6-Aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 5)

Linker 5 was synthesized following the same procedures as. Linker 1 asdescribed in Example 1. (1.8 g, yield: 20% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 11.10 (s, 1H), 7.76 (s, 3H), 7.58 (t, J=7.2 Hz, 1H),7.10 (d, J=8.4 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 6.54 (t, J=6.0 Hz, 1H),5.07-5.03 (m, 1H), 3.37-3.27 (m, 2H), 2.88-2.78 (m, 3H), 2.61-2.50 (m,2H) 2.04-2.01 (m, 1H) 1.57-1.52 (m, 4H), 1.40-1.30 (m, 4H). MS (ESI)m/z=373.1 [M+H]⁺.

Example 6:4-((7-Aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 6)

Linker 6 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (2.0 g, yield: 25% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 11.05 (br, 1H), 7.94-7.56 (m, 4H), 7.10-7.02 (m, 2H),6.52 (t, J=6.0 Hz, 1H), 5.07-5.02 (m, 1H),3.32-3.27 (m, 2H),2.88-2.77(m, 1H), 2.75-2.61 (m, 2H), 2.60-2.50 (m, 2H), 2.04-2.02 (m, 1H),1.59-1.50 (m, 4H), 1.35-1.30 (m, 6H). MS (ESI) m/z=387.2 [M+H]⁺.

Example 7:4-((8-Aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 7)

Linker 7 was synthesized following the same procedures as. Linker 1 asdescribed in Example 1. (1.1 g, yield: 18% over 2 steps). ¹H NMR (400MHz, DMSO-d₆) δ 11.10 (s, 1H), 7.69-7.56 (m, 4H), 7.09 (d, J=8.4 Hz,1H), 7.03 (d, J=6.8 Hz, 1H), 6.52 (t, J=6.0 Hz, 1H), 5.07-5.03 (m, 1H),3.34-3.26 (m, 2H), 2.89-2.85 (m, 1H), 2.76 (s, 2H), 2.61-2.56 (m, 2H),2.04-2.00 (m, 1H), 1.59-1.49 (m, 4H), 1.35-1.27 (m, 8H). MS (ESI)m/z=401.2 [M+H]⁺.

Example 8:4-((2-(2-Aminothoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 8)

Linker 8 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (2.0 g, yield: 23% over 2 steps). ¹H NMR (400MHz, DMSO-d₆) δ 10.10 (s, 1H), 7.88 (s, 3H), 7.60 (t, J=8.0 Hz, 1H),7.17 (d, 8.4 Hz, 1H), 7.06(d, J=6.8 Hz, 1H), 6.40 (d, J=5.6 Hz, 1H),5.05 (dd, J=5.2, 12.8 Hz, 1H), 3.67-3.62 (m, 4H), 3.54-3.50 (m, 2H),3.00 (s, 2H), 2.90-2.85 (m, 1H), 2.62-2.50 (m, 2H), 2.03 (t, J=7.6 Hz,1H). MS (ESI) m/z=361.1 [M+H]⁺.

Example 9:4-((2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-2-(2-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 9)

Linker 9 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (1.1 g, yield: 17% over 2 steps). ¹H NMR (400MHz, DMSO-6) δ 11,11 (d, 1H), 7.84 (s, 3H), 7.62-7.58 (m, 1H), 7.15 (d,J=8.8 Hz, 1H), 7.05 (d, J=6.8 Hz, 1H), 6.62-6.59 (m, 1H), 5,08-5.04 (m,1H), 3.65-3.59 (m, 8H), 3.50-3.46 (m, 2H), 2.97-2.86 (m, 3H), 2.62-2.51(m, 2H), 2.05-1.99 (m, 1H). MS (ESI) m/z=405.2 [M+H]⁺.

Example 10:4-((2-(2-(2(2-Aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 10)

Linker 10 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (1.3 g, yield: 17% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 11.11 (s, 1H), 7.83 (s, 3H), 7.61-7.57 (m, 1H), 7.15 (d,J=8.8 Hz, 1H), 7.05 (d, J=6.8 Hz, 1H), 6.62-6.59 (m, 1H), 5.08-5.04 (m,1H), 3.64-3.45 (m, 14H), 2.97-2.86 (m, 3H), 2.62-2.51(m, 2H), 2.08-2.01(m, 1H). MS (ESI) m/z=449.2 [M+H]⁺.

Example 11:4-(14-Amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 11)

Linker 11 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (1.2 g, yield: 16% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 11.11 (s, 7.84 (s, 3H), 7.61-7.57 (m, 1H), 7.15 (d,J=8.8 Hz, 1H), 7.05 (d, J=6.8 Hz, 1H), 6.61 (s, 1H), 5.08-5.04 (m, 1H),3.64-3.47 (m, 18H), 2.99-2.86 (m, 3H), 2.62-2.51(2H), 2.08-2.01 (m, 1H).MS (ESI) m/z=493.2 [M+H]⁺.

Example 12:4-((17-Amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 12)

Linker 12 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (1.2 g, yield: 15% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 11.11 (s, 1H), 7.82 (s, 3H), 7.61-7.57 (m, 1H), 7.15 (d,J=8.4 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.61-6.59 (m, 1H), 5,08-5.03 (m,1H), 3.64-147 (m, 22H), 3.00-2.86 (m, 3H), 2.62-2.51 (m, 2H), 2.05-2.02(m, 1H). MS (ESI) m/z=537.2 [M+H]⁺.

Example 13:(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (Linker13)

Linker 13 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (840 mg, yield: 16% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 11.07 (s, 1H), 7.52 (t, J=7.6 Hz, 1H), 6.99-6.88 (m,3H), 5.04 (dd, J=5.2, 12.8 Hz, 1H), 3.73 (s, 2H), 2.93-2.83 (m, 1H),2.61-2.50 (m, 2H), 2.02 (t, J=5.6 Hz, 1H). MS (ESI) m/z=330.1 [M+H]⁻.

Example 14:3-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoicacid (Linker 14)

Linker 14 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (1.42 g, yield: 24% over 2 steps). ¹H NMR (400MHz, DMSO-d₆) δ 11.61 (br, 1H), 11.08(s, 1H), 7.58 (dd, J=7.2, 8.8 Hz,1H), 7.15 (d, J=8.8 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.64 (s, 1H), 5.05(dd, J=5.2, 12.8 Hz, 1H), 3.53 (t, J=6.4 Hz, 2H), 2.92-2.83 (m, 1H),2.61-2.50 (m, 4H), 2.05-2.00 (m, 1H). MS (ESI) m/z=346.1 [M+H]⁺.

Example 15:4-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoicacid (Linker 15)

Linker 15 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (1.27 g, yield: 13% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 12.12 (br, 1H), 11.08 (s, 1H), 7.58 (dd, J=7.2, 8.81 Hz,1H), 7.13 (d, J=8.8 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 6.64 (t, J=6.0 Hz,1H), 5.05 (dd, J=5.6, 12.8 Hz, 1H), 3.33 (q, J=6.8 Hz, 2H), 2.93-2.83(m, 1H),2.61-2.50 (m, 2H), 2.31 (t, J=6.8 Hz, 2H), 2.07-2.00 (m, 1H),1.83-1.75 (m, 2H). MS (ESI) m/z=360.1 [M+H]⁺.

Example 16:5-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoicacid (Linker 16)

Linker 16 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (1.4 g, yield: 15% over 2 steps). ¹H NMR (400MHz, DMSO-d₆) δ 12.02 (br, 1H), 11.08 (s, 1H), 7.58 (dd, J=8.8, 7.2 Hz,1H), 7.10 (d, J=8.4 Hz, 1H), 7.02 (d, J=7.2 Hz, 1H), 6.64 (t, J=5.6 Hz,1H), 5.07-5.03 (m, 1H), 3.32-3.02 (m, 2H), 2.93-2.84 (m, 1H), 2.61-2.54(m, 2H), 2.28-2.25 (m, 2H), 2.05-2.01 (m, 1H), 1.60-1.51 (m, 4H). MS(ESI) m/z=374.1 [M+H]⁺.

Example 17:6-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoicacid (Linker 17)

Linker 17 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (1.43 g, yield: 18% over 2 steps). ¹H NMR (400MHz, DMSO-d₆) δ 11.97 (s, 1H), 11.08 (s, 1H), 7.57 (dd, J=7.2, 8.8 Hz,1H), 7.08 (d, J=8.8 Hz, 1H), 7.02 (d, J=7.2 Hz, 1H), 6.52 (t, J=6.0 Hz,1H), 5.05 (dd, J=5.6, 12.8 Hz, 1H), 3.30 (q, J=6.8 Hz, 2H), 2.93-2.83(m, 1H), 2.61-2.50 (m, 2H), 2.32 (t, J=7.2 Hz, 2H), 2.07-2.00 (m, 1H),1.61-1.50 (m, 4H), 1.39-1.33 (m, 2H). MS (ESI) m/z=388.1 [M+H]⁺.

Example 18:7-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoicacid (Linker 18)

Linker 18 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (2.3 g, yield: 24% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 11.92 (br, 1H), 11.08 (s, 1H). 7.57 (t, J=8.0 Hz, 1H),7.13 (d, J=8.8 Hz, 1H), 7.03 (d, J=6.8 Hz, 1H), 6.52 (t, J=5.6 Hz, 1H),5.05 (dd, J=5.6, 12.8 Hz, 1H), 3.30 (q, J=6.4 Hz, 2H), 2.93-2.83 (m,1H), 2.61-2,50 (m, 2H), 2.31 (t, J=7.2 Hz, 2H), 2.07-2.00 (m, 1H),1.58-1.48 (m, 4H), 1.34-1.31 (m, 4H). MS (ESI) m/z=402.1 [M+H]⁺.

Example 19:8-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoicacid (Linker 19)

Linker 19 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (1.14 g, yield: 35% over 2 steps), ¹H NMR (400MHz, DMSO-d6) δ 11.94(s, 1H), 11.08 (s, 1H), 7.57 (t, J=8.0 Hz, 1H),7.08 (d, J=8.4 Hz, 1H), 7.02 (d, J=6.8 Hz, 1H), 6.52 (t, J=5.6 Hz, 1H),5.05 (dd, J=5.6, 12.8 Hz, 1H), 3.31-3.26 (m, 2H), 2.93-2.83 (m, 1H),2.61-2.50 (m, 2H), 2.19 (t, J=7.2 Hz, 2H), 2.05-2.00 (m, 1H), 1.58-1.47(m, 4H), 1.35-1.25 (s, 6H). MS (ESI) m/z=416.1 [M+H]⁺.

Example 20:3-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoic acid (Linker 20)

Linker 20 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (3.5 g, yield: 18% over 2 steps), ¹H NMR (400MHz, DMSO-d6) δ 12.18 (s, 1H), 11.08 (s, 1H), 7.58 (dd, J=7.2 Hz, 8.8Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6,58 (t, J=5.6Hz 1H), 5.05 (dd, J=6.4 Hz, 12.8 Hz, 1H), 3.67-3.58 (m, 4H), 3.47-3.43(m, 2H), 2.93-2.84 (m, 1H), 2.61-2.45 (m, 4H), 2.07-2.01 (m, 1H). MS(ESI) m/z=390.1 [M+H]⁺.

Example 21:3-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoicacid (Linker 21)

Linker 21 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (2.0 g, yield: 24% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 12.13 (s, 1H), 11.08 (s, 1H), 7.58 (dd, J=7.2 Hz, 8.4Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.04 (d, J=6.8 Hz, 1H), 6.60 (t, J=6.0Hz 1H), 5.05 (dd, J=5.2 Hz, 12.4 Hz, 1H), 3.63-3.44 (m, 10H), 2.88-2.85(m, 1H), 2.61-2.49 (m,2H), 2.44-2.41 (m, 2H), 2.04-2.01 (m, 1H). MS(ESI) m/z=434.1 [M+H]⁺.

Example 22:3-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoicacid (Linker 22)

Linker 22 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (3.2 g, yield: 42% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 12.14 (s, 1H), 11.08 (s, 1H), 7.58 (dd, J=7.2 Hz, 8.4Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.04 (d, J=6.8 Hz, 1H), 6.60 (t, J=6.0Hz, 1H), 5.05 (dd, J=5.2 Hz, 12.8 Hz, 1H), 3.63-3.45 (m, 14H), 2.88-2.85(m, 1H), 2.61-2.49 (m, 2H), 2.44-2.40 (m, 2H), 2.04-2.01 (m, 1H). MS(ESI) m/z=478.2 [M+H]⁺.

Example 23:1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oicacid (Linker 23)

Linker 23 was synthesized following the same procedures as Linker 1 asdescribed in Example 1. (2.3 g, yield: 31% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 12.14 (s, 1H), 11.08 (s, 1H), 7.58 (dd, J=7.2 Hz, 8.8Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.60 (t, J=6.0Hz, 1H), 5.05 (dd, J=5.2 Hz, 12.8 Hz, 1H), 3.63-3.48 (m, 18H),2.898-2.85 (m, 1H), 2.61-2.49 (m, 2H), 2.44-2.41 (m, 2H), 2.04-2.01 (m,1H). MS (ESI) m/z=522.2 [M+H]⁺.

Example 24:1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oicacid (Linker 24)

Linker 24 was synthesized following the same procedures as Linker 1 asdescribed as Example 1. (2.4 g, yield: 36% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 11.09 (s, 1H), 7.58 (dd, J=7.2, 8.4 Hz, 1H), 7.13 (d,J=8.4 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.60 (t, J=5.6 Hz, 1H), 5.05 (dd,J=5.6, 12.8 Hz, 1H), 3.64-3.46 (m, 22H), 2.43-2.83 (m, 1H), 2.61-2.50(m, 2H), 2.44-2.40 (m, 2H), 2.02 (t, J=6.4 Hz, 1H). MS (ESI) m/z=566.2[M+H]⁺.

Example 25:(2S,4R)-1-((S)-2-(2-Aminoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 25)

Step 1: To a solution of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylathazol-5-yl)benzyl)pyrrolidine-2-carboxamide(2.00 g, 4.67 mmol), 2-(tert-butoxycarbonyl)amino) acetic acid (900 mg,5.14 mmol) and triethylamine (TEA) (3.2 mL, 23.35 mmol) in DCM/DMF (225mL/11 mL) were added EDCI (1.07 g, 5.60 mmol), HOBt (756 mg, 5.60 mmol)at 0° C. The mixture was stirred at room temperature for 16 hours. Themixture was poured into water and extracted with DCM. The combinedorganic layers were concentrated and the residue was purified bychromatography on a silica gel column (DCM/MeOH=20/1, v/v) to give thedesired product tert-butyl(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)carbamate(1.5 g, yield: 55%). MS (ESI) m/z=588.2 [M+H]⁺.

Step 2: To a solution of tert-butyl(2-(((S)-1-(2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)carbamate(1.50 g, 2.56 mmol) in ethylacetate (EtOAc) (30 mL) was added HCl/EtOAc(100 mL). The mixture was stirred at room temperature for 3 hours andfiltered to give the desired product which was dissolved in water (100mL) and lyophilized to give(2S,4R)-1-((S)-2-(2-aminoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamidehydrochloride (Linker 25) (1.07 g, yield: 80%). ¹H NMR (400 MHz,DMSO-d₆) δ 9.29 (s, 1H), 8.72 (s, 1H), 8.56 (d, J=9.2 Hz, 1H), 8.26 (s,3H), 7.38-7.47 (m, 4H), 4.61 (d, J=9.2 Hz, 1H), 4.36-4.47 (m, 3H),4.20-4.25 (m, 1H), 3.60-3.70 (m, 4H), 2.46 (s, 3H), 2.10-2.05 (m, 1H),1.97-1.89 (m, 1H), 0.95 (s, 9H). MS (ESI) m/z=488.3 [M+H]⁺.

Example 26:(2S,4R)-1-((S)-2-(3-Aminopropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 26)

Linker 26 was synthesized following the same procedures as Linker 25 asdescribed in Example 25. (1.38 g, yield: 37% over 2 steps). ¹H NMR (400MHz, DMSO-d₆) δ 9.36 (s, 1H), 8.68 (s, 1H), 8.26 (d, J=9.2 Hz, 1H), 8.16(s, 3H), 7.49-7.39 (m, 4H), 4.53 (d, J=9.2 Hz, 1H), 4.47-4.35 (m, 3H),4.24-4.19 (m, 1H), 3.69-3.60 (m, 2H), 2.94-2.93 (m, 2H), 2.64 (t, J=7.2Hz, 2H), 2.48 (s, 3H), 2,06-2.01 (m, 1H), 1.92-1.85 (m, 1H), 0.95 (s,9H). MS (ESI) m/z=502.3 [M+H]⁺.

Example 27:(2S,4R)-1-((S)-2-(4-Aminobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 27)

Linker 27 was synthesized following the same procedures as Linker 25 asdescribed in Example 25. (1.38 g, yield: 46% over 2 steps). ¹H NMR (400MHz, DMSO-d₆) δ 9.66 (s, 1H), 8.74 (t, J=6.0, 1H), 8.25 (s, 3H), 8.03(d, J=9.2 Hz, 1H), 7.49-7.41 (m, 4H), 4.53 (d, J=9.2 Hz, 1H), 4.51-4.35(m, 3H), 4.29-4.24 (m, 1H), 3.71-3.65 (m, 2H), 2.79-2.77 (m, 2H), 2.52(s, 3H), 2.45-2.27 (m, 2H), 2.12-2.07 (m, 1H), 1.94-1.80 (m, 3H), 0.94(s, 9H). MS (ESI) m/z=516.0 [M+H]⁺.

Example 28:(2S,4R)-1-((S)-2-(5-Aminopentanamido)-3,3-dimethylbulanol)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 28)

Linker 28 was synthesized following the same procedures as Linker 25 asdescribed in Example 25. (1.50 g, yield: 57% over 2 steps). ¹H NMR (400MHz, DMSO-d₆) δ 9.52 (s, 1H), 8.73 (t, J=11.6 Hz, 1H), 8.20 (s, 3H),7.95 (d, J=9.6 Hz, 1H), 7.43-7.50 (m, 4H), 4.55 (d, J=9.2 Hz, 1H),4.38-4.50 (m, 3H), 4.23-4.29 (m, 1H), 3.64-3.71 (m, 2H), 2.74-2.78 (m,2H).,2.51 (s, 3H), 2.30-2.35 (m, 1H), 2.18-2.23 (m, 1H), 2.07-2.12 (m,1H),1.88-1.95 (m, 1H), 1.58 (d, J=4.4 Hz, 4H), 0.96 (s, 9H). MS (ESI)m/z=530.1 [M+H]⁺.

Example 29:(2S,4R)-1-((S)-2-(6-Aminohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 29)

Linker 29 was synthesized following the same procedures as Linker 25 asdescribed in Example 25. (2.70 g, yield: 87% over 2 steps). ¹H NMR (400MHz, DMSO-d6): δ 9.36 (s, 1H), 8.69 (t, J=6.4 Hz, 1H), 8.12 (brs, 3H),7.92 (d, J=9.6 Hz, 1H), 7.44 (dd, J=13.6, 8.4 Hz, 4H), 4.54 (d, J=9.6Hz, 1H), 4.48-4.39 (m, 2H), 4.36 (brs, 1H), 4.28-4.19 (m, 1H), 3.72-3.60(m, 2H), 2.79-2.67 (m, 2H), 2.49 (s, 3H), 2.31-2.21 (m, 1H), 2.20-2.12(m, 1H), 2.10-2.01(m, 1H), 1.94-1.85 (m, 1H), 1.62-1.54 (m, 2H),1.53-1.44 (m, 2H), 1.34-1.22 (m, 2H), 0.94 (s, 9H). MS (ESI) m/z=544.3[M+H]⁺.

Example 30:(2S,4R)-1-((S)-2-(7-Aminoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 30)

Linker 30 was synthesized following the same procedures as Linker 25 asdescribed in Example 25. (2.13 g, yield: 76% over 2 steps). ¹H NMR (400MHz, DMSO-d6): δ 9.45 (s, 1H), 8.70 (t, J=6.0 Hz, 1H), 8.14 (brs, 3H),7.86 (d, J=9.2 Hz, 1H), 7.44 (dd, J=12.8, 8.4 Hz, 4H), 4.54 (d, J=9.2Hz, 1H), 4.49-4.40 (m, 2H), 4.36 (brs, 1H), 4.29-4.20 (m, 1H), 3.71-3.61(m, 2H), 2.78-2.67 (m, 2H), 2.50 (s, 3H), 2.31-2.22 (m, 1H), 2.21-2.13(m, 1H), 2.11-2.03 (m, 1H), 1.95-1.85 (m, 1H), 1.60-1.44 (m, 4H),1.35-1.18 (m, 4H), 0.94 (s, 9H). MS (ESI) m/z=558.3 [M+H]⁺.

Example 31:(2S,4R)-1-((S)-2-(8-Aminooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 31)

Linker 31 was synthesized following the same procedures as Linker 25 asdescribed in Example 25. (1.81 g, yield: 65% over 2 steps). ¹H NMR (400MHz, DMSO-d6): δ 9.35 (s, 1H), 8.69 (t, J=6.0 Hz, 1H), 8.11 (brs, 3H),7.88 (d. J=9.2 Hz, 1H), 7.44 (dd, J=14.0, 8.4 Hz, 4H), 4.54 (d, J=9.6Hz, 1H), 4.48-4.39 (m, 2H), 4.36 (brs, 1H), 4.27-4.20 (m, 1H), 3.71-3.60(m, 2H), 2.78-2.68 (m, 2H), 2.49 (s, 3H), 2.31-2.22 (m, 1H), 2.18-2.11(m, 1H), 2.09-2.01(m, 1H), 1.94-1.85 (m, 1H), 1.58-1.44 (m, 4H),1.32-1.19 (m, 6H), 0.94 (s, 9H). MS (ESI) m/z=572.3 [M+H]⁺.

Example 32:(2S,4R)-1-((S)-2-(9-Aminononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 32)

Linker 32 was synthesized following the same procedures as Linker 25 asdescribed in Example 25. (2.32 g, yield: 80% over 2 steps). ¹H NMR (400MHz, DMSO-d6): δ 9.30 (s, 1H), 8.67 (t, J=6.4 Hz, 1H), 8.10 (brs, 3H),7.88 (d, J=9.2 Hz, 1H), 7.43 (dd, J=14.0, 8.8 Hz, 4H), 4.55 (d, J=9.2Hz, 1H), 4.48-4.39 (m, 2H), 4.35 (brs, 1H), 4.28-4.19 (m, 1H), 3.71-3.60(m, 2H), 2.77-2.67 (m, 2H), 2.48 (s, 3H), 2.31-2.22 (m, 1H), 2.17-2.10(m, 1H), 2.09-2.01 (m, 1H), 1.94-1.85 (m, 1H), 1.60-1.40 (m, 4H),1.33-1.19 (m, 8H), 0.94 (s, 9H). MS (ESI) m/z=586.3 [M+H]⁺.

Example 33:(2S,4R)-1-((S)-2-(10-Aminodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 33)

Linker 33 was synthesized following the same procedures as Linker 25 asdescribed as Example 25. (2.29 g, yield: 77% over 2 steps). ¹H NMR (400MHz, DMSO-d6): δ 9.41 (s, 1H), 8.67 (t, J=6.0 Hz, 1H), 8.14 (brs, 3H),7.85 (d, J=8.8 Hz, 1H), 7.44 (dd, J=13.6, 8.8 Hz, 4H), 4.54 (d, J=8.8Hz, 1H), 4.48-4.39 (m, 2H), 4.36 (brs, 1H), 4.29-4.20 (m, 1H), 3.71-3.60(m, 2H), 2.78-2.67 (m, 2H), 2.49 (s, 3H), 2.32-2.22 (m, 1H), 2.17-2.11(m, 1H), 2.10-2.01 (m, 1H), 1.95 (m, 1H), 1.62-1.40 (m, 4H), 1.34-1.16(m, 10H), 0.94 (s, 9H). MS (ESI) m/z=600.4 [M+H]⁺.

Example 34:(2S,4R)-1-((S)-2-(11-Aminoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 34)

Linker 34 was synthesized following the same procedures as Linker 25 asdescribed as Example 25. (1.10 g, yield: 37% over 2 steps). ¹H NMR (400MHz, DMSO-d6): δ 8.99 (s, 1H), 8.61 (t, J=6.4 Hz, 1H), 7.87 (d, J=8.8Hz, 1H), 7.41 ((dd, J=17.6, 8.0 Hz, 4H), 4.55 (d, J=9.6 Hz, 1H),4.49-4.40 (m, 2H), 4.36 (brs, 1H), 4.26-4.17 (m, 1H), 3.70-3.64 (m, 2H),2.59-2.52 (m, 2H), 2.45 (s, 3H), 2.31-2.22 (m, 1H), 2.16-2.08 (m, 1H),2.06-1.99 (m, 1H), 1.96-1.86 (m, 1H), 1.56-1.42 (m, 2H),1.39-1.30(m,2H), 1.28-1.19 (m, 12H), 0.94 (s, 9H). MS (ESI) m/z=614.4 [M+H]⁺.

Example 35:(2S,4R)-1-((S)-2-(2-(2-Aminoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 35)

Linker 35 was synthesized following the same procedures as Linker 25 asdescribed in Example 25. (1.35 g, yield: 55% over 2 steps). ¹H NMR (400MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.70 (t, J=6.0 Hz, 1H), 8.35-8.14 (m, 3H),7.78 (d, J=9.6 Hz, 1H), 7.47-7.38 (m, 4H), 4.61 (d, J=9.6 Hz, 1H),4.49-4.34 (m, 3H), 4.30-4.21 (m, 1H), 4.09-3.99 (m, 2H),3.75-3.58 (m,4H), 3.06-2.94 (m, 2H), 2.48 (s, 3H), 2.13-2.03 (m, 1H), 1.95-1.85 (m,1H), 0.95 (s, 9H). MS (ESI) m/z=532.0 [M+H]⁺.

Example 36:(2S,4R)-1-((S)-2-(3-(2-Aminoethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 36)

Linker 36 was synthesized following the same procedures as Linker 25 asdescribed in Example 25. (1.32 g, yield: 49% over 2 steps). ¹H NMR (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.57 (t, J=6.0 Hz, 1H), 8.03 (d, J=8 Hz,1H), 7.85 (s, 3H), 7.43-7.37(m, 4H), 4.57 (d, J=9.2 Hz, 1H), 4.46-4.31(m, 3H), 4.26-4.20 (m, 1H), 3.69-3.55 (m, 6H), 3.99-2.95 (m, 2H),2.60-2.56 (m, 1H), 2.46-2.42 (m, 4H), 2.05-2.03 (m, 1H), 1.93-1.92 (m,1H), 0.95 (s, 9H). MS (ESI) m/z=546.0 [M+H]⁺.

Example 37:(2S,4R)-1-((S)-2-(2-(2-(2-Aminoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylithiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 37)

Linker 37 was synthesized following the same procedures as Linker 25 asdescribed as Example 25. (1.2 g, yield: 49% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 9.38 (s, 1H), 8.78 (t, J=6.0 Hz, 1H), 8.18 (s, 3H),7.59-7.37 (m, 5H), 4.58 (d, J=9.6 Hz, 1H), 4.49 (t, J=8.2 Hz, 1H),4.42-4.26 (m, 3H), 4.09-3.95 (m, 2H), 3.72-3.55 (m, 8H), 2.99-2.92 (m,2H), 2.49 (s, 3H), 2.15-2.04 (m, 1H), 1.95-1.85 (m, 1H), 0.95 (s, 9H).MS (ESI) m/z=576.1 [M+H]⁺.

Example 38:(2S,4R)-1-((S)-2-(3-(2-(2-Aminoethoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 38)

Linker 38 was synthesized following the same procedures as Linker 25 asdescribed as Example 25. (1.34 g, yield: 49% over2 steps). ¹H NMR (400MHz, DMSO-d₆) δ 902 (s, 1H), 8.58 (t, J=6.0 Hz, 1H), 7.94 (d, J=8 Hz,1H), 7.82 (s, 3H), 7.42-7.30(m, 4H), 4.58 (d, J=9.2 Hz, 1H), 4.60-4.37(m, 3H), 4.25-4.31 (m, 1H), 3.70-3.50 (m, 10H), 3.00-2.96 (m, 2H),2.57-2.55 (m, 1H), 2.45(s, 3H), 2.41-2.38 (m, 1H), 2.06-2.04(m, 1H),1.95-1.93 (m, 1H), 0.95 (s, 9H). MS (ESI) m/z=590.1 [M+H]⁺.

Example 39:(2S,4R)-1-((S)-14-Amino-2-tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 39)

Linker 39 was synthesized following the same procedures as Linker 25 asdescribed as Example 25. (1.53 g, yield: 56% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 9.01 (s, 1H), 8.59 (t, 6.0 Hz, 1H), 7.81 (s, 3H),7.48-7.41 (m, 5H), 4.58 (d, J=9.6 Hz, 1H), 4.47-4.26 (m, 4H), 3.99 (s,2H), 3.70-3.58 (m, 12H), 3.0-2.96 (m, 2H), 2.46 (s, 3H), 2.11-2.06 (m,1H), 1.95-1.88 (m, 1H), 0.96 (s, 9H). MS (ESI) m/z=621.1 [M+H]⁺.

Example 40:(2S,4R)-1-((S)-1-Amino-14-(tert-butyl)-12-oxo-3,6,9-trioxa-13-azapentadecan-15-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 40)

Linker 40 was synthesized following the same procedures as Linker 25 asdescribed as Example 25. (1.52 g, yield: 51% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 9.01 (s, 1H), 8.57 (t, J=6.0 Hz, 1H), 7.91 (d, J=9.2 Hz,1H), 7.81 (s, 3H), 7.44-7,38 (m, 4H), 4.58-4.55 (m, 1H), 4.45-4.36 (m,3H), 4.25-4.21 (m, 1H), 3.70-3.48 (m, 14H), 3.00-2.97 (m, 2H), 2.59-2.52(m, 1H), 2.46 (s, 3H), 2.39-2.34 (m, 1H), 2.08-2.03 (m, 1H), 1.95-1.88(m, 1H), 0.94 (s, 9H). MS (ESI) m/z=633.8 [M+H]⁺.

Example 41:(2S,4R)-1-((S)-1-Amino-17-tert-butyl)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecan-18-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 41)

Linker 41 was synthesized following the same procedures as Linker 25 asdescribed as Example 25. (1.12 g, yield: 37% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 8.98 (s, 1H), 8.58 (t, J=5.6 Hz, 1H), 7.92 (d, J=9.2 Hz,1H), 7.44-7.38 (m, 4H), 4.56 (d, J=9.2 Hz, 1H), 4.47-4.41 (m, 2H),4.38-4.34 (m, 1H), 4.26-4.19 (m, 1H), 3.70-3.55 (m, 5H), 3.53-3.45 (m,14H), 3.35 (t. J=5.6 Hz, 2H), 2.64 (t, J=5.6 Hz, 2H), 2.58-2.50 (m, 1H),2.45 (s, 3H), 2.40-2.35 (m, 1H), 2.08-2.00 (m, 1H), 1.94-1.91 (m, 1H),0.94 (s, 9H). MS (ESI) m/z=678.1 [M+H]⁺.

Example 42:(2S,4R)-1-((S)-1-Amino-20-(tert-butyl)-18-oxo-3,6,9,12,15-pentaoxa-19-azahenicosan-21-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(Linker 42)

Linker 42 was synthesized following the same procedures as Linker 25 asdescribed as Example 25. (1.1 g, 1.52 mmol, yield: 32% over 2 steps). ¹HNMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H), 8.67 (t, J=16 Hz, 1H), 8.14 (br,3H). 7.91 (d, J=9.2 Hz, 1H), 7.39-7.48 (m, 4H), 4.53 (d, J=9.2 Hz, 1H).4.39-4.46 (m, 2H), 4.36-4.34 (m, 1H), 4.20-4.25 (m, 1H), 3.45-3.68 (m,22H), 2.91-2.95 (m, 2H), 2.52-2.58 (m, 1H), 2.47 (s, 3H), 2.32-2.39 (m,1H), 2.03-2.08 (m,1H), 1.85-1.92 (m, 1H), 0.92 (s, 9H). MS (ESI)m/z=722.4 [M+H]⁺.

Example 43:4-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutanoicacid (Linker 43)

A mixture of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(1.0 g, 2.3 mmol) and succinic anhydride (465 mg, 4.65 mmol) in pyridine(5 mL) was stirred at room temperature for overnight. The mixture wasconcentrated. The residue was purified by flash chromatography(reversed-phase, MeCN/H₂O) to give the tide compound Linker 43 (1.05 g,yield: 86%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 8.99 (s, 1H),8.58 (t, J=6.0 Hz, 1H), 7.96 (d, J=9.2 Hz, 1H), 7.43-7.37 (m,4H), 5.13(d, J=3.6 Hz, 1H), 4.53 (d, J=9.2 Hz, 1H), 4.46-4.40 (m, 2H), 4.34 (s,1H), 4.21 (dd, J=16.0, 5.2 Hz, 1H), 3,69-3,60 (m, 2H), 2.45 (s, 3H),2.44-2.33 (m, 4H), 2.06-2.01 (m, 1H),1.93-1.87 (m, 1H), 0.93 (s, 9H).¹³C NMR (100 MHz, DMSO-d6): δ 173.83, 171.92, 170.86, 169.56, 151.41,147.70, 139,48, 131.15, 129,63, 128.62, 127.41, 68.87, 58.70, 56.44,56.34, 41.65, 37.91, 35.35, 29.74, 29.25, 26.35, 15.92. MS (ESI)m/z=531.2 [M+H]⁺.

Example 44:5-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentanoicacid (Linker 44)

Linker 44 was synthesized following the same procedures as Linker 43 asdescribed as Example 43. (1.5 g, yield: 79%). ¹H NMR (400 MHz, DMSO-d₆):δ 8.99 (s, 1H), 8.59 (t., J=6.0 Hz, 1H), 7.91 (d, J=9.2 Hz, 1H),7.44-7.37 (m, 4H), 5.16 (brs, 1H), 4.54 (d, J=9.2 Hz, 1H), 4.47-4.42 (m,2H), 4.36 (s, 1H), 4.21 (dd, J=16.0, 5.2 Hz, 1H), 3.7-3.64 (m, 2H), 2.45(s, 3H), 2.31-2.14 (m, 4H), 2.07-2.02 (m, 1H), 1.94-1.81 (m, 1H).1.74-1.68 (m, 2H), 0.94 (s, 9H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.18,171.94, 171.63, 169.66, 151.41, 147.70, 139.46, 131.15, 129.61, 128.62,127.41, 68.86, 58.69, 56.38, 41.65, 37.91, 35.16, 34.03, 33.10, 26,35,20.89, 15.92. MS (ESI) m/z=543.2 [M−H]⁻.

Example 45:6-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-6-oxohexanoicacid (Linker 45)

Linker 45 was synthesized following the same procedures as Linker 25 asdescribed as Example 25. (1.2 g, yield: 55% over 2 steps). ¹H NMR (400MHz, CDCl₃) δ 8.68 (s, 1H), 7.75 (s, 1H), 7.32-7.27 (m, 5H), 4.64-4.57(m, 3H), 4.56-4.50 (m, 1H), 4.28-4.25 (m, 1H), 4.02-3.99 (m, 1H),3.71-3.68 (m, 1H), 2.47 (s, 3H), 2.24-2.18 (m, 6H),1.59-1.48 (m, 4H),0.96 (s, 9H). MS (ESI) m/z=559.3 [M+H]⁺.

Example 46:7-(((S)-1-((2S,4R)-4-Hydroxy-2((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoicacid (Linker 46)

Linker 46 was synthesized following the same procedures as Linker 45 asdescribed as Example 45. (1.1 g, yield: 33% over 2 steps). ¹H NMR (400MHz, CDCl₃) δ 8.67 (s, 1H), 7.56-7.55 (m, 1H) 7.34-7.30 (m, 5H),4.68-4.59 (m, 3H), 4.59-4.51 (m, 1H), 4.25 (dd, J=4.8 Hz, 15.2 Hz, 1H),4.06-4.03 (m, 1H), 3.70-3.68 (m, 1H), 2.46 (s, 3H), 2.31-2.11 (m, 6H),1.55-1.51 (m, 4H), 1.29-1.24 (m, 2H), 0.94 (s, 9H). MS (ESI) m/z=573.1[M+H]⁺.

Example 47:8-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxonctanoicacid (Linker 47)

Linker 47 was synthesized following the same procedures as Linker 45 asdescribed as Example 45. (1.08 g, yield: 52% over 2 steps). ¹H NMR (400MHz, DMSO-d6) δ 8.99 (s, 1H), 8.55 (t, J=2.4 Hz, 1H), 7.83 (d, J=9.2 Hz,1H), 7.44-7.38 (m, 4H), 4.55 (d, J=9.6 Hz, 1H), 4.52-4.41 (m, 2H),4.36(s, 1H), 4.25-4.21 (m, 1H), 3.67-3.66 (m, 2H), 2.45 (s, 3H),2.30-1.91 (m, 6H), 1.49-1.47 (m, 4H), 1.26-1.24 (m, 4H), 0.92 (s, 9H).MS (ESI ) m/z=587.3 [M+H]⁺.

Example 48:9-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononanoicacid (Linker 48)

Linker 48 was synthesized following the same procedures as Linker 45 asdescribed in Example 45. (1.16 g, yield: 44% over 2 steps). ¹H NMR (400MHz, CDCl₃) δ 8.70 (s, 1H), 7.55 (s, 1H), 7.33-7.27 (m, 4H), 7.08 (d,J=8.0 Hz, 1H), 4.68-4.52 (m, 4H), 4.31-4.27 (m, 1H), 4.08-4.05 (m, 1H),3.69-3.67 (m, 2.48 (s, 3H), 2.33-2.11 (m, 6H), 1.60-1.47 (m, 4H),1.29-1.20 (m, 6H), 0.96 (s, 9H). MS (ESI) m/z=601.1 [M+H]⁺.

Example 49:10-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecanoicacid (Linker 49)

Linker 49 was synthesized following the same procedure as Linker 45 asdescribed as Example 45. (1.1 g, yield: 35%). ¹H NMR (400 MHz, DMSO-d₆):δ 8.99 (s, 1H), 8.58 (t, J=6.0 Hz, 1H), 7.85 (d, J=9.2 Hz, 1H),7.43-7.37 (m, 4H), 4.54 (d, J=9.2 Hz, 1H), 4.47-4.41 (m, 2H), 4.35 (s,1H), 4.21 (dd, J=16.0, 5.6 Hz, 1H), 3.69-3.63 (m, 2H), 2.45 (s, 3H),2.29-2.09 (m, 4H), 2.03-2.01 (m, 1H), 1.94-1.88 (m, 1H), 1.47 (m, 4H),1.24 (b, 8H), 0.94 (s, 9H). ¹³C NMR (100 MHz, DMSO-d₆): δ 172.07,171.92, 169.69, 151.41, 147.70, 139.48, 131.14, 129.62, 128.61, 127.40,68.84, 58.67, 56.32, 56.26, 41.64, 37.93, 35.18, 34,85, 28.62, 26.36,25.39, 15.93. MS (ESI) m/z=615.3 [M+H]⁺.

Example 50:11-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecanoicacid (Linker 50)

Linker 50 was synthesized following the same procedure as Linker 45 asdescribed as Example 45. (1.1 g, yield: 50%). ¹H NMR (400 MHz, DMSO-d₆):δ 8.99 (s, 1H), 8.58 (t, J=6.0 Hz, 1H), 7.85 (t, J=9.2 Hz, 1H),7.37-7.43 (m, 4H), 4.56-4.19 (m, 5H), 3.70-3.60 (m, 2H), 2.45 (s,3H),2.27-1.90(m, 6H), 1.49-1.45 (m, 4H), 1.23 (m, 10H), 0.93 (s, 9H).¹³C NMR (100 MHz, DMSO-d₆): δ 174.59, 172.07, 171.92, 169.69, 151.42,147.70, 139.49, 131.14, 129.62, 128.61, 127.41, 68.84, 58.67, 56.32,56.25, 41.64, 37.93, 35.19, 34.85, 33.80, 28.82, 28.70, 28.68, 28.62,28.55, 26.37, 25.42, 24.55, 15.93. MS (ESI) m/z=629.4 [M+H]⁺.

Example 51:3-(3-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)propanoicacid (Linker 51)

Linker 51 was synthesized following the same procedure as Linker 45 asdescribed in Example 45. (1.1 g, yield: 42%). ¹H NMR (400 MHz, DMSO-d6)δ 8.98 (s, 1H), 8.55 (t, J=6.0 Hz, 1H), 7.91 (d, J=9.2 Hz, 1H),7.41-7.37 (m, 4H), 4.55-4,53 (m, 1H), 4.45-4,40 (m, 2H), 4.35 (s, 1H),4.24-4.19 (m, 1H). 3.68-3.52 (m, 6H), 2.54-2.56 (m, 1H), 2.45-2.37 (m,5H),2.34-2.30 (m, 1H), 2.05-2.00 (m, 1H), 1.93-1.86 (m, 1H), 0.93 (s,9H). MS (ESI) m/z=575 [M+H]⁺.

Example 52:2-(2-(((S)-1-((2S,4R)-4-Hvdroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobtitan-2-yl)amino)-2oxyethoxy)aceticacid (Linker 52)

Linker 52 was synthesized following the same procedure as Linker 43 asdescribed as Example 43. (1.2 g, yield: 63%). ¹H NMR (400 MHz, DMSO-d₆)δ 12.81 (br s, 1H), 8.98 (s, 1H), 8.58 (t, J=6.0 Hz, 1H), 7.60 (d, J=9.6Hz, 1H), 7.45-7.35 (m, 4H), 5.14 (br, 1H), 4.58-4.55 (m, 1H), 4.46-4.36(m, 3H), 4.28-4.26 (m, 1H), 4.14 (s, 2H), 4.04 (s, 2H), 3.69-3.60 (m,2H), 2.44 (s, 3H) 2.08-2.03 (m, 1H), 1.93-1.87 (m, 1H), 0.95 (s, 9H). MS(ESI) m/z=547 [M+H]⁺.

Example 53:3-(2-(3-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)ethoxy)propanoicacid (Linker 53)

Linker 53 was synthesized following the same procedures as Linker 45 asdescribed as Example 45. (1.4 g, yield 23% over 2 steps). ¹H NMR (400MHz, DMSO-d₆): δ 8.98 (s, 1H), 8.56 (t, J=6.0 Hz, 1H), 7.91 (d, J=9.2Hz, 1H), 7.43-7.37 (m, 4H), 4.55 (d, J=9.6 Hz, 1H), 4.46-4.41 (m, 2H),4.35 (s, 1H), 4.29-4.20 (m, 1H), 3.70-3.57 (m, 7H),3.50-3.45 (m, 5H),2.57-2.55 (m, 1H), 2.45 (s, 3H), 2.43-2.41 (m, 1H), 2.37-2.32 (m, 1H).2.09-2.01 (m, 1H), 1.94-1.87 (m, 1H), 0.94 (s, 9H). MS (ESI) m/z=619.3[M+H]⁺.

Example 54:(2-(2-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-yl)amino)-2-oxoethoxy)ethoxy)aceticacid (Linker 54)

Linker 54 was synthesized following the same procedures as Linker 53 asdescribed as Example 53. (1.13 g, yield 20% over 2 steps). ¹H NMR (400MHz, DMSO-d₆): δ 8.98 (s, 1H), 8.60 (t, J=6.0 Hz, 1H), 7.49 (d, J=9.2Hz, 1H), 7.40 (s, 4H), 4.57 (d, J=9.2 Hz, 1H), 4.47-4.36 (m, 3H),4.28-4.23 (m, 1H), 4.05-3.93 (m, 4H), 3.69-3.61 (m, 6H), 2.45 (s, 3H),2.08-2.03 (m, 1H), 1.94-1.87 (m, 1H), 0.94 (s, 9H). MS (ESI) m/z=591.2[M+H]⁺.

Example 55:(S)-15-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,77,10-trioxa-14-azaheptadecanoicacid (Linker 55)

Linker 55 was synthesized following the same procedure as Linker 45 asdescribed in Example 45. (1.7 g, yield 37%). ¹H NMR (400 MHz, DMSO-d₆):δ 8.99 (s, 1H), 8.56 (t, J=6.0 Hz, 1H), 7.91 (d, J=9.6 Hz, 1H),7.44-7.38 (m, 4H), 4.56 (d, J=9.2 Hz, 1H), 4.47-4.42 (m, 2H), 4.36 (s,1H), 4.25-4.20 (m, 1H), 3.70-3.55 (m, 6H), 3.50-3.46 (m, 8H), 2.58-2.51(m, 3H), 2.45-2.42(m, 5H), 2.40-2.33 (m, 1H), 2.07-2.02 (m, 1H),1.94-1.88(m, 1H), 0.94 (s, 9H). LCMS (ESI) m/z=661.0 [M−H]⁻.

Example 56:(S)-13-((2S,4R)-4-Hydroxy-2-((4-(4-methylithiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecanoicacid (Linker 56)

Linker 56 was synthesized following the same procedures as Linker 45 asdescribed as Example 45. (1.21 g, yield 31% over 2 steps). ¹HNMR (400MHz, CDCl₃): δ 8.68 (s, 1H), 7.80-7.71 (m, 11H), 7.41-7.33 (m, 5H),4.71-7.65 (m, 1H), 4.61-4.50 (m, 3H), 4.37-4.33 (m, 1H), 4.07-3.94(m,5H), 3.77-3.58 (m, 10H), 2.51 (s, 3H), 2.38-2.30 (m, 1H), 2.24-2.19(m, 1H), 0.98 (s, 9H). LCMS (ESI) m/z=635.0 [M+H]⁺.

Example 57:(S)-18-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbonoyl)pyrrolidine-1-carbonyl)-19,19-dimethyl-16-oxo-4,7,10,13-tetraoxa-17-azaicosanoicacid (Linker 57)

Linker 57 was synthesized following the same procedure as Linker 45 asdescribed as Example 45. (1.6 g, yield 43%). ¹H NMR (400 MHz, CDCl₃): δ8.69 (s, 1H), 7.55-7.52 (m, 1H), 7.47-7.45 (m, 1H), 7.36 (s, 4H),4.70-4.66 (m, 1H), 4.62-4.57 (m, 2H), 4.50 (s, 1H), 4.34-4.29 (m, 1H),4.12-4.09 (m, 1H), 3.75-3.48 (m, 18H), 2.56-2.47 (m, 7H), 2.40-2.33 (m,1H), 2.23-2.18 (m, 1H), 0.96 (s, 9H). MS (ESI) m/z=707.1 [M+H]⁺.

Example 58:(S)-21-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbonyl)pyrrolidine-1-carbonyl)-22,22-dimethyl-19-oxo-4,7,10,13,16-pentaoxa-20-azatricosanoicacid (Linker 58)

Linker 58 was synthesized following the same procedure as Linker 45 asdescribed as Example 45. (1.2 g, yield: 23%). ¹H NMR (400 MHz, DMSO-d₆)δ 8.98 (s, 1H), 8.57 (t, J=6.0 Hz, 1H), 7.91 (d, J=9.6 Hz, 1H),7.43-7.31 (m, 4H), 4.56-4.53 (m, 1H), 4.45-4.35 (m, 3H), 4.24-4.19 (m,1H), 3.69-3.55 (m, 6H), 3.49-3.47 (m, 16H), 2.57-2.53 (m, 1H), 2.45 (s,3H), 2.39-2.32 (m, 3H), 2.06-2.01 (m, 1H), 1.93-1.86 (m, 1H), 0.95 (s.9H). MS (ESI) m/z=751 [M+H]⁺.

Example 59:(S)-19-(2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-20,20-dimethyl-17-oxo-3,6,9,12,15-pentaoxa-18-azahenicosanoicacid (Linker 59)

Linker 59 was synthesized following the same procedure as Linker 45 asdescribed as Example 45. (1.3 g, yield: 39%). ¹H NMR (400 MHz, DMSO-d₆)δ 8.98 (s, 1H), 8.69 (t, J=6.0 Hz, 1H), 7.45 (d, J=9.6 Hz, 1H),7.43-7.37 (m, 4H), 4.57-4.55 (m, 1H), 4.47-4,34 (m, 3H), 4.27-4.22 (m,1H), 3.97 (s, 2H), 3.68-3.65 (m, 2H), 3.61-3.48 (m, 18H), 2.45 (s, 3H),2.09-2.04 (m, 1H), 1.92-1.86(m, 1H), 0.94 (s, 9H). MS (ESI) m/z=723[m+H]⁺.

Example 60. Synthesis of TRKi-1

Step 1

To a solution of 3-cyano-4-fluorophenylboronic acid (1) (3.3 g, 20 mmol)in toluene (30 mL) were added potassium phosphate (8.5 g, 40 mmol) andtetrakis(triphenylphosphine)palladium (462 mg, 0.4 mmol), followed by3,5-difluorobenzyl bromide (2) (4.2 g, 10 mmol). The reaction mixturewas heated at 100° C. for 2 hours. After the reaction was completed, theresulting black mixture was diluted with ether (200 mL), washed withsaturated aqueous ammonium chloride (2×50 mL) and brine (3×50 mL). Theorganic layer was dried over sodium sulphate, evaporated and purified bysilica gel flash chromatography (n-hexane/ethyl acetate 95:5) to yield5-(3,5-difluorobenzyl)-2-fluorobenzonitrile (3) (2.9 g, yield 59%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) 7.90 (dd, J=6.0 Hz, 2.0 Hz, 1H),7.73-7.69 (m, 1H), 7.46 (t, J=8.8 Hz, 1H), 7.09-7.04 (m, 3H), 4.01 (s,2H). MS (ESI) m/z=248.2[M+H]⁺.

Step 2

A mixture of 5-(3,5-difluoro-benzyl)-2-fluoro-benzonitrile (3) (2.9 g,11.74 mmol) and hydrazine hydrate (1.76 mL, 35.22 mmol) in n-butanol(200 mL) was heated at 120° C. overnight. The reaction mixture wasdiluted with water and ethyl acetate. The organic phase was washed twicewith brine, dried and concentratted. The resulting residue was purifiedby silica gel chromatography(DCM/MeOH=95:5) to afford5-(3,5-difluorobenzyl)-1H-indazol-3-amine (4) (2.7 g, yield 89%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.32 (s, 1H), 7.52 (s, 1H),7.18-7.11 (m, 2H), 7.04 (t, J=9.6 Hz, 1H), 6.95-6.93 (m, 2H), 5.26 (s,2H), 4.00 (s, 2H). MS (ESI) m/z=260.0 [M+H]⁺.

Step 3

A solution of 4-fluoro-2-nitro-benzoic acid (5) (10 g, 54 mmol),di-tert-butyl-dicarbonate (23.6 g, 108 mmol) and 4-dimethylaminopyridine(1.98 g, 16.2 mmol) in tert-butanol (100 mL) and dichloromethane (100mL) was stirred at room temperature overnight. The reaction mixture wasthen diluted with ethyl acetate (500 mL), washed with 1N hydrochloricacid (500 mL), water (500 mL) and brine (500 mL). The organic phase wasdried over sodium sulfate, concentrated and purified by silica gelchromatography column (DCM/MeOH=20/1) to affordtert-butyl4-fluoro-2-nitrobenzoate (6) as a yellow solid (10.7 g, yield82%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.04 (dd, J=8.4 Hz, 2.8 Hz, 1H), 7.94(dd, J=8.8 Hz, 1.6 Hz, 1H), 7.71 (ddd, J=8.4 Hz, 2.4 Hz, 1H),1.50 (s,9H). MS (ESI) m/z=242.2 [M+H]⁺.

Step 4

To a solution of piperazine (13.7 g, 159.75 mmol) in tetrahydrofuran(150 mL) was added tert-butyl 4-fluoro-2-nitrobenzoate (6) (7.7 g, 31.95mmol). The mixture was stirred at 70° C. for 16 h, before being pouredinto water and extracted with ethyl acetate (10mL×3). The combinedorganic layers were washed with water, brine, dried over sodium sulfateand concentrated to give crude tert-butyl2-nitro-4-(piperazin-1-yl)benzoate (7) (9.7 g, yield 99%) as yellow oil,which was used in the next step without further purification. MS (ESI)m/z=308.1 [M+H]⁺.

Step 5

To a solution of 2-nitro-4-piperazin-1-yl-benzoic acid tert-butyl ester(7) (13.5 g, 44.12 mmol) in dichloromethane (200 mL) were addedtriethylamine (13.4 g, 132.35 mmol) and trifluoroacetic anhydride (18.5g, 88.24 mmol) at 0° C. The mixture was stirred at room temperature for1 h. The solvent was evaporated to give a residue, which was purified byflash chromatography silica gel column (petroleum ether/ethylacetate=1/1) to givetert-butyl2-nitro-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate(8) (16.5 g, yield: 93%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆); δ7.72 (d, J=9.2 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H), 7.16 (dd, J=2.8, 9.2 Hz,1H), 3.72-3.70 (m, 4H), 3.56-3.52 (m, 4H), 1.45 (s, 9H). MS (ESI)m/z=404.3 [M+H]⁺.

Step 6

tert-butyl2-nitro-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate(8) (8.0 g, 19.85 mmol) was dissolved in methanol (150 ml), before Pd/C(1.0 g) was added. The resulting mixture was stirred under hydrogen atatmosphere pressure for 16 h. The solution was filtered over a pad ofcelite and washed with methanol several times. The filtrate wasconcentrated under vacuum to afford tert-butyl2-amino-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate (9) (6.3 g,yield 85%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.51 (d,J=9.2 Hz, 1H), 6.47 (br, 2H), 6.20 (dd, J=2.8, 9.2 Hz, 1H), 6.13 (d,J=2.8 Hz, 1H), 3.71-3.69 (m, 4H), 3.31-3.29 (m, 4H), 1.50 (s, 9H). MS(ESI) m/z=374.0 [M+H]⁺.

Step 7

To a solution of tert-butyl2-amino-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate (6.3 g,16.89 mmol) in dichloromethane (9) (150 mL) were addedtetrahydro-pyran-4-one (2.1 g, 21.11 mmol), trifluoroacetic acid (3.5mL) and tetramethylammonium triacetoxyborohydride (6.7 g, 25.34 mmol).The mixture was stirred at room temperature for 16 h, before beingwashed sequentially with 0.5 N hydrochloric acid, 0.5 N sodiumhydroxide, and a saturated solution of sodium bicarbonate. The organiclayer was dried over sodium sulfate and concentrated to affordtert-butyl2-((tetrahydro-2H-pyran-4-yl)amino)-4-(4-(2,2,2-triflouroacytel)piperazin-1-yl)benzoate(10) (3.5 g, yield 50%) as a pale yellow solid. ¹HNMR (400 MHz,DMSO-d₆): δ 7.72 (d, J=7.6 Hz, 1H), 7.60 (d, J=9.2Hz,1H), 6.20 (dd,J=2.4, 9.2 Hz, 1H), 6.09 (d, J=2.0 Hz, 1H), 3.86-3.82 (m, 2H), 3.70-3.69(m, 5H), 3.52-3.46 (m, 2H), 3.39-3.38 (m, 4H), 1.97-1.94 (m, 2H), 1.50(s, 9H), 1.43-1.34 (m, 2H). MS (ESI) m/z=458.1 [M+H]⁺.

Step 8

tert-butyl2-((tetrahydro-2H-pyran-4-yl)amino)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate(10) (3.8 g, 8.32 mmol) was dissolved in dichloromethane (100 ml) andcooled to 0° C. To the resulting solution was added triethylamine (1.3g, 12.47 mmol) followed by a slow addition of trifluoroacetic anhydride(2.3 g, 10.81 mmol). After being stirred for 1h, the reaction wasquenched with water and diluted with DCM. The organic layer was washedwith a saturated solution of aqueous sodium bicarbonate and brine. Theorganic layer was dried over sodium sulfate, concentrated and purifiedby silica gel chromatography column (petroleum ether/ethyl acetate=2/1)to give tert-butyl2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate(11) (4.2 g, yield 91%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆): δ7.85 (d, J=8.8 Hz, 1H), 7.08 (dd, J=2.4, 8.8 Hz, 1H), 6.85 (d, J=2.4 Hz,1H), 4.52-4.44 (m, 1H), 3.89-3.77 (m, 2H), 3.75-3.72 (m, 4H), 3.55-3.49(m, 4H), 345-3.32 (m, 2H), 1.99-1.97 (m, 1H), 1.65-1.53 (m, 1H),1.48-1.45 (m, 1H), 1.45 (s, 9H), 1.08-0.96 (m,1H). MS (ESI) m/z=554.1[M+H]⁺.

Step 9

To a solution oftert-butyl2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoate(11) (4.2 g, 7.59 mmol) in DCM (50 ml) was added TFA (50 mL) at 0° C.After the reaction was stirred at room temperature for 16 h, the solventwas removed under vacuum. The residue was washed with diethyl ether togive2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoicacid (12) (3.5 g, yield 93%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 12.70 (s, 1H), 7.90(d, J=8.8 Hz, 1H), 7.06 (dd, J=2.8, 9.2 Hz,1H),6.86 (d, J=2.01 Hz, 1H), 4.51-4.43 (m, 1H), 3.88-3.79 (m,2H), 3.75-3.72(m, 4H), 3.55-3.41 (m, 6H), 1.97-1.94 (m, 1H), 1.64-1.49 (m, 2H),1.12-1.02 (m, 1H). MS (ESI) m/z=498.0 [M+H]⁺.

Step 10

To a suspension of2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzoicacid (12) (3.5 g, 7.04 mmol) in dry dichloromethane (150 mL) were addedcatalytic amount of N,N-dimethylformamide, oxalyl chloride (2.7 g, 21.13mmol) at 0° C. The mixture was stirred for about 1.5 h before beingconcentrated. The residue was azeotroped with dry dichloromethane twice.The acyl chloride was dissolved in dry dichloromethane (50 mL). Theresulting suspension was added slowly to a solution of5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (1.86 g, 7.04 mol) andtriethylamine (2.2 g, 21.13 mmol) in dry tetrahydrofuran (100 mL) at −20C. The mixture was stirred at room temperature for 16 h before beingconcentrated. The resulting residue was purified by silica gelchromatography column (petroleum ether/ethyl acetate=1/1) to giveN-(5-(3,5-difluorobenzl)-1H-indazol-3-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzamide(13) (4.0 g, yield 77%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ12.70 (s, 1H), 10.58 (s, 1H) 7.86 (d, J=8.4 Hz, 1H), 7.43-7.41(m, 2H),7.27 (d, J=9.2 Hz, 1H), 7.18-7.11 (m, 1H), 7.04-6.99 (m, 1H), 6.95-6.93(m, 3H), 4.47-4.41 (m, 1H), 4.01 (s, 2H), 3.80-3.72 (m,4H), 3.22-3.17(m, 4H), 3.51-3.47 (m, 4H), 1.93-1.90 (m, 1H), 1.67-1.64 (m,1H),1.60-1.50 (m, 1H), 1.37-1.26 (m, 1H). MS (ESI) m/z=739.0 [M+H]⁺.

Step 11

To a solution ofN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzamide(13) (4.0 g. 5.42 mmol) in methanol (100 mL) was added potassiumcarbonate (3.7 g, 27.1 mmol). The mixture was stirred at roomtemperature for 2 h before being filtered. The filtrate was evaporatedand the residue was purified by silica gel chromatography(DCM/MeOH=10:1)to giveN-(5-(3,5-difluorobenzl)-1H-indazol-3-yl)-4-(piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TRKi-1) (1.9 g, yield: 64%) as a blue solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.68 (s, 1H), 10.12 (s, 1H), 8.31 (d, J=6.8 Hz, 1H), 7.81(d, J=8.4 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4Hz, 1H), 7.03-6.98 (m, 3H), 6.23 (d, J=8.4 Hz, 1H), 6.13 (s, 1H), 4.04(s, 2H), 3.83-3.80 (m, 2H), 3.68-3.62 (m, 1H), 3.52-3.47 (m, 2H),3.22-3.17 (m, 4H), 2.87-2.80 (m, 4H), 1.95-1.92 (m, 2H), 1.36-1.34 (m,2H). MS (ESI) m/z=547.2 [M+H]⁺.

Example 61. Synthesis of TRKi-2

To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (14) (4.6 g,20.0 mmol) in dimethylsuphoxide (40 mL) were added potassium fluoride(20 g, 362 mmol) and (R)-2-(3-fluorophenyl)pyrrolidine (15) (3 g, 18.2mmol). The resulting mixture was stirred at 100° C. for 12 h. Themixture was diluted with ethyl acetate, washed with water. The organiclayer was concentrated and the residue was purified by columnchromatography (ethyl acetate) to give(R)-3-bromo-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine(16) (1.8 g, yield 28%) as a yellow solid. MS (ESI) m/z=360.9 [M+H]⁺.

Step 2

To a solution of(R)-3-bromo-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine(16) (2.17 g, 6.03 mmol) in toluene (50 mL) were added2-fluoro-6-(tributylstannyl)pyridine (17) (3.5 g, 9.04 mmol) andtetrakis(triphenylphosphine)palladium (566 mg, 0.49 mmol). The resultingmixture was stirred at 110° C. for 12 h under nitrogen atmosphere beforebeing poured into ethyl acetate and sat. potassium fluoride. Afterstirring at room temperature for 2 h, the mixture was extracted withethyl acetate. The combined organic layers were concentrated andpurified by column chromatography (hexanes: ethyl acetate=1:1 to 100%ethyl acetate) to give(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine(18) (2.2 g, yield 97%) as yellow oil. MS (ESI) m/z=378.0 [M+H]⁺.

Step 3

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine(18, 1.4 g, 3.7 mmol) in dimethylsuphoxide (40 mL) was added piperazine(6.4 g, 74 mmol), followed by potassium fluoride (8.6 g, 148 mmol). Theresulting mixture was stirred at 130° C. for 12 h before being pouredinto water and extracted with ethyl acetate. The combined organic layerswere washed with water, concentrated and purified by columnchromatography (dichloromethane:methanol=10:1 to 5:1) to give desiredproduct as a yellow oil, which was dissolved in hydrochloric acid/ethylacetate (4 M), and stirred for 1 h, concentrated to give(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazinehydrochloride (TRKi-2) (1.168 g, yield 66%) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆): δ 9.62 (s, 2H), 8.63 (s, 1H), 8.21 (s, 1H),7.62-7.19 (m, 6H), 7.06-7.01 (m, 2H), 5.26-5.25 (m, 1H), 4.07-4.02 (m,1H), 3.86-3.85 (m, 4H), 3.74-3.72 (m, 1H), 3.16-3.15 (m, 4H), 2.08-2.07(m, 2H), 1.92-1.91 (m, 2H). MS (ESI) m/z=444.2 [M+H]⁺.

Example 62. Synthesis of TRKi-3

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-piperazin-1-yl)pyridine-2-yl)imidazo[1,2-b]pyridazine(TRKi-2) (1 g, 2,25 mmol) in DMF (40 ml) were added K₂CO₃(621 mg, 4.50mmol) and tert-butyl2-bromoacetate (510 mg, 2.60 mmol). The resultingmixture was stirred at room temperature for 3 hours. After the amine wastotally consumed, the reaction was poured into water (300 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with saturated brine (100 mL) and dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography to give tert-butyl(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetate(1.05 g, yield: 84%) as a light yellow solid. MS (ESI) m/z: 558.7[M+H]⁺.

To a solution oftert-butyl(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetate(1 g, 1.79 mmol) in dichloromethane (20 ml) was added trifluoroaceticacid (20 mL). The resulting mixture was stirred at room temperature for3 hours. After the starting material was totally consumed, the reactionwas evaporated under reduced pressure. The resulting residue waspurified by reverse-phase chromatography to give(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazol[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetic acid (TRKi-3) (860 mg,yield: 79% over two steps) as a light yellow solid. MS (ESI) m/z: 502.6[M+H]⁺.

Example 63. Synthesis of TRKi-4

To a solution ofN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (TRKi-1) (1.0 g, 1.83 mmol) in DMF(40 ml) were added K₂CO₃(505 mg, 3.66 mmol) and tert-butyl2-bromoacetate(357 mg, 1.83 mmol). The resulting mixture was stirred atroom temperature for 3 hours. After the amine was totally consumed, thereaction was poured into water (300 mL) and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with saturated brine(100 mL) and dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography to givetert-butyl2-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)acetate (1.03 g, yield: 85%) asa light yellow solid. MS (ESI) m/z: 661.3 [M+H]⁺.

To a solution of tert-butyl2-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)acetate(1 g, 1.51 mmol) in dichloromethane (20 ml) was added trifluoroaceticacid (20 mL). The resulting mixture was stirred at room temperature for3 hours. After the starting material was totally consumed, the reactionwas evaporated under reduced pressure. The resulting residue waspurified by reverse-phase chromatography to give2-(4-(4-((5((3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)aceticacid (TRKi-4) (790 mg, yield 73%) as a light yellow solid. MS (ESI) m/z:605.3 [M+H]⁺.

Example 64:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-053)

To a solution of4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoicacid (657 mg, 1.83 mmol) DMSO (30 mL) were added NMM (926 mg, 9.15mmol,), HOAT (373 mg, 2.74 mmol), EDCI (526 mg, 2.74 mmol) andN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TRKi-1) (1 g, 1.83 mmol) sequentially. The resulting solution wasstirred at room temperature for 16 hours, before the reaction was pouredinto water (200 mL) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with saturated brine (100 mL) anddried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby reverse-phase chromatography to give N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-053) (1.2 g, yield 74%) as a tight yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 10.28 (s, 1H), 7.89 (d, J=9.0 Hz, 1H), 7,59(dd, J=8.4, 7,2 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.26 (d,J=9.9 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.08-6.94 (m, 4H), 6.47-6.28 (m,2H), 5.06 (dd, J=12.9, 5.3 Hz, 1H), 4.04 (s, 2H), 3.84 (s, 2H), 3.63 (s,5H), 3.57 (s, 1H), 3.46 (t, J=10.5 Hz, 3H), 3.40-3.24 (m, 6H), 3.17 (s,1H), 2.87 (d, J=12.0 Hz, 1H), 2.57 (dd, J=19.7, 10.5 Hz, 1H), 2.47 (d,J=6.8 Hz, 2H), 2.08-1.76 (m, 5H), 1.48-1.34 (m, 2H), 1.23 (s, 1H). MS(ESI) m/z: 888.6 [M+H]⁺.

Example 65:(2S,4R)-1-((S)-2-(6-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-001)

CPD-001 was synthesized following the standard procedure for preparingCPD-053 (12 mg, yield 76%). MS (ESI) m/z: 984.7 [M+H]⁺.

Example 66:(2S,4R)-1-((S)-2-(2-(2-(2-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-002)

CPD-002 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 69%). MS (ESI) m/z: 1016.6 [M+H]⁺.

Example 67:(2S,4R)-1-((S)-2-(tert-butyl)-20-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,20-dioxo-6,9,12,15,18-pentaoxa-3-azaicosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-003)

CPD-003 was synthesized following the standard procedure for preparingCPD-053 (14 mg, yield 72%). MS (ESI) m/z: 118.8 [M+H]⁺.

Example 68:(2S,4R)-1-((S)-2-(7-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-004)

CPD-004 was synthesized following the standard procedure for preparingCPD-053 yield 70%). MS (ESI) m/z: 997.8 [M+H]⁺.

Example 69:(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-005)

CPD-005 was synthesized following the standard procedure for preparingCPD-053 (13 mg, yield 76%). MS (ESI) m/z: 1176.6 [M+H]⁺.

Example 70:(2S,4R)-1-((S)-2-(4-4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-006)

CPD-006 was synthesized following the standard procedure for preparingCPD-053 (9 mg, yield 63%). MS (ESI) m/z: 956.4 [M+H]⁺.

Example 71:(2,S,4R)-1-((S)-2-(3-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-007)

CPD-007 was synthesized following the standard procedure for preparingCPD-053 (12 mg, yield 73%). MS (ESI) m/z: 1000.5 [M+H]⁺.

Example 72:(2S,4R)-1-((S)-2-(2-(2-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-008)

CPD-008 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 75%). MS (ESI) m/z: 972.4 [M+H]⁺.

Example 73:2-(2,6-Dioxopiperidin-3-yl)-4((7-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazol[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione(CPD-009)

CPD-009 was synthesized following the standard procedure for preparingCPD-053 (13 mg, yield 79%). MS (ESI) m/z: 827.4 [M+H]⁺.

Example 74:2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazol[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione(CPD-010)

CPD-010 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 73%). MS (ESI) m/z: 903.4 [M+H]⁺.

Example 75:(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-011)

CPD-011 was synthesized following the standard procedure for preparingCPD-053 (15 mg, yield 81%). MS (ESI) m/z: 1060.5 [M+H]⁺.

Example 76:(2S,4R)-1-((S)-2-(5-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-012)

CPD-012 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 72%). MS (ESI) m/z: 970.4 [M+H]⁺.

Example 77:2-(2,6-Dioxopiperidin-3-yl)-4-((4-(4-(6-(6-((R)-2-(3-flourophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4-oxobutyl)amino)isoindoline-1,3-dione (CPD-013)

CPD-013 was synthesized following the standard procedure for preparingCPD-053 (8 mg, yield 69%). MS (ESI) m/z: 785.3 [M+H]⁺.

Example 78:2-(2,6-Dioxopiperidin-3-yl)-4-((5-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione(CPD-014)

CPD-014 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 73%). MS (ESI) m/z: 799.3 [M+H]⁺.

Example 79:2-(2,6-Dioxopiperidin-3-yl)-4-((6-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-6-oxohexyl)amino)isoindoline-1,3-dione(CPD-015)

CPD-015 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 74%). MS (ESI) m/z: 813.4 [M+H]⁺.

Example 80:(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-016)

CPD-016 was synthesized following the standard procedure for preparing;CPD-053 (13 mg, yield 73%). MS (ESI) m/z: 1088.5 [M+H]⁺.

Example 81:(2,S,4R)-1-((S)-2-(10-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-017)

CPD-017 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 70%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),8.21 (s, 1H), 7.97(d, J=9.9 Hz, 1H), 7,54 (dd, J=20.1, 12.4 Hz, 2H),7.39 (dd, J=14.1, 7.9 Hz, 1H), 7.26-7.08 (m, 2H), 7.02 (dt, J=15.3, 7.8Hz, 2H), 6.76 (d, J=8.6 Hz, 1H), 6.58 (s, 1H), 5.19 (d, J=5.9 Hz, 1H),5.03 (dd, J=12.8, 5.2 Hz, 1H), 4.01 (d, J=5.0 Hz, 1H), 3.76-3.66 (m,2H), 3.65-3.50 (m, 8H), 3.45 (s, 3H), 2.94-2.79 (m, 1H), 2.77 (d, J=4.9Hz, 1H), 2.64 (t, J=6.4 Hz, 1H), 2.56 (d, J=7.2 Hz, 1H), 2.53 (s, 1H),2.47-2.43 (m, 1H), 2.33 (s, 1H), 2.02 (dd, J=15.7, 8.4 Hz, 3H), 1.90 (s,1H), 1.27 (d, J=25.3 Hz, 3H), 0.84 (d, J=6.8 Hz, 1H). MS (ESI) m/z:1040.5 [M+H]⁺.

Example 82:(2S,4R)-1-((S)-2-(9-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-9-oxondecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-018)

CPD-018 was synthesized following the standard procedure for preparingCPD-053 (9 mg, yield 72%). MS (ESI) m/z: 1026.5 [M+H]⁺.

Example 83:(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pryidin-2-yl)piperazin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-019)

CPD-019 was synthesized following the standard procedure for preparingCPD-053 (12 mg, yield 78%). MS (ESI) m/z: 1132.5 [M+H]⁺.

Example 84:(2S,4R)-1-((S)-2-(3-(2-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-020)

CPD-020 was synthesized following the standard procedure for preparingCPD-053 (10 mg, yield 71%). MS (ESI) m/z: 1044.5 [M+H]⁺.

Example 85:2-(2,6-Dioxopiperidin-3-yl)-4-((15-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)isoindoline-1,3-dione(CPD-021)

CPD-021 was synthesized following the standard procedure for preparingCPD-053 (12 mg, yield 76%). MS (ESI) m/z: 947.4 [M+H]⁺.

Example 86:(2S,4R)-1-((S)-2-(11-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-11-oxoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-022)

CPD-022 was synthesized following the standard procedure for preparingCPD-053 (13 mg, yield 78%). MS (ESI) m/z: 1054.5 [M+H]⁺.

Example 87:2-(2,6-Dioxopiperidin-3-yl)-4-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione(CPD-023)

CPD-023 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 72%). MS (ESI) m/z: 757.3 [M+H]⁺.

Example 88:2-(2,6-Dioxopiperidin-3-yl)-4-((3(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-8-oxooctyl)amino)isoindoline-1,3-dione(CPD-024)

CPD-024 was synthesized following the standard procedure for preparingCPD-053 (13 mg, yield 75%). MS (ESI) m/z: 841.4 [M+H]⁺.

Example 89:2-(2,6-Dioxopiperidin-3-yl)-4-((18-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoetadecyl)amino)isoindoline-1,3-dione(CPD-025)

CPD-025 was synthesized following the standard procedure for preparingCPD-053 (14 mg, yield 76%). MS (ESI) m/z: 991.4 [M+H]⁺.

Example 90:2-(2,6-Dioxopiperidin-3-yl)-4-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione(CPD-026)

CPD-026 was synthesized following the standard procedure for preparingCPD-053 (12 mg, yield 71%). MS (ESI) m/z: 771.3 [M+H]⁺.

Example 91:2-(2,6-Dioxopiperidin-3-yl)-4-((2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)isoindoline-1,3-dione(CPD-027)

CPD-027 was synthesized following the standard procedure for preparingCPD-053 (14 mg, yield 77%). MS (ESI) m/z: 815.3 [M+H]⁺.

Example 92:2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione(CPD-028)

CPD-028 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 72%). MS (ESI) m/z: 859.4 [M+H]⁺.

Example 93:(2S,4R)-1-((S)-2-(8-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-029)

CPD-029 was synthesized following the standard procedure for preparingCPD-053 (14 mg, yield 76%). MS (ESI) m/z: 1012.5 [M+H]⁺.

Example 94:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-030)

CPD-030 was synthesized following the standard procedure for preparingCPD-053 (10 mg, yield 72%). MS (ESI) m/z: 918.4 [M+H]⁺.

Example 95:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan)-15-oyl)piperazin-1-yl)-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-031)

CPD-031 was synthesized following, the standard procedure for preparingCPD-053 (13 mg, yield 76%). MS (ESI) m/z: 1050.4 [M+H]⁺.

Example 96:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-032)

CPD-032 was synthesized following the standard procedure for preparingCPD-053 (10 mg, yield 71%). MS (ESI) m/z: 962.4 [M+H]⁺.

Example 97:(2S,4R)-1-((S)-2-(8-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-033)

CPD-033 was synthesized following the standard procedure for preparingCPD-053 (13 mg, yield 73%). MS (ESI) m/z: 1115.5 [M+H]⁺.

Example 98:(2S,4R)-1-((S)-2-(10-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-034)

CPD-034 was synthesized following the standard procedure for preparingCPD-053 (12 mg, yield 71%). MS (ESI) m/z: 1143.6 [M+M]⁺.

Example 99:(2S,4R)-1-((S)-2-(11-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-035)

CPD-035 was synthesized following the standard procedure for preparingCPD-053 (13 mg, yield 75%). MS (ESI) m/z: 1157.6 [M+H]⁺.

Example 100:(2S,4R)-1-(S)-2-(5-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-036)

CPD-036 was synthesized following the standard procedure for preparingCPD-053 (10 mg, yield 71%). MS (ESI) m/z: 1073.5 [M+H]⁺.

Example 101:(2S,4R)-1-((S)-2-(9-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-9-oxononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-037)

CPD-037 was synthesized following the standard procedure for preparingCPD-053 (13 mg, yield 76%). MS (ESI) m/z: 1129.5 [M+H]⁺.

Example 102:(2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-038)

CPD-038 was synthesized following the standard procedure for preparingCPD-053 (10 mg, yield 72%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),9.65 (s, 1H), 8.06 (d, J=99.8 Hz, 1H), 7.87-7.50 (m, 1H), 7.42-7.18 (m,1H), 7.18 (s, 1H), 7.24-7.01 (m, 3H), 6.87 (dd, J=73.2, 17.7 Hz, 1H),6,96-6.71 (m, 1H), 6.96-6.61 (m, 1H), 6.52 (s, 1H), 5.32 (s, 1H), 5.11(dd, J=53.0, 7.1 Hz, 1H), 4.00 (s, 1H), 3.68-3.57 (m, 10H), 3.30 (m,4H), 2.86-2.77 (m, 4H), 2.58 (d, J=16.2 Hz, 1H), 2.35 (s, 1H), 1.97 (d,J=59.9 Hz, 2H), 1.54 (d, J=22.7 Hz, 4H), 1.28 (d, J=37.7 Hz, 6H), 0.91(s, 1H), 0.85 (s, 1H). MS (ESI) m/z: 1147.5 [M+H]⁺.

Example 103:(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-039)

CPD-039 was synthesized following the standard procedure for preparingCPD-053 (13 mg, yield 77%). MS (ESI) m/z: 1191.5 [M+H]⁺.

Example 104:(2S,4R)-1-((S)-2-(tert-butyl)-20-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,20-dioxo-6,9,12,15,18-pentaoxa-3-azaicosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-040)

CPD-040 was synthesized following the standard procedure for preparingCPD-053 (10 mg, yield 71%). MS (ESI) m/z: 1251.6 [M+H]⁺.

Example 105:(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-041)

CPD-041 was synthesized following the standard procedure for preparingCPD-053 (12 mg, yield 78%). MS (ESI) m/z: 1235.6 [M+H]⁺.

Example 106:(2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-042)

CPD-042 was synthesized following the standard procedure for preparingCPD-053 (13 mg, yield 76%). MS (ESI) m/z: 1119.5 [M+H]⁺.

Example 107:(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-043)

CPD-043 was synthesized following the standard procedure for preparingCPD-053 (10mg, yield 72%). MS (ESI) m/z: 1279.6 [M+H]⁺.

Example 108:(2S,4R)-1-((S)-2-(6-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-044)

CPD-044 was synthesized following the standard procedure for preparingCPD-053 (13 mg, yield 76%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),8.09 (s, 1H), 7.88 (d, J=9.8 Hz, 1H), 7.68-7.54 (m, 2H), 7.49 (s, 1H),7.38 (dd, J=14.1, 7.9 Hz, 1H), 7.17 (t, J=8.9 Hz, 3H), 7.03 (t, J=9.2Hz, 2H), 6.78 (t, J=19.4 Hz, 2H), 5.17 (d, J=7.9 Hz, 1H), 5.06 (dd,J=12.8, 5.3 Hz, 1H), 4.00 (dd, J=9.9, 5.2 Hz, 1H), 3.63 (dt, J=43.4,13.8 Hz, 9H), 2.87 (dd, J=21.7, 9.7 Hz, 1H), 2.67-2.53 (m, 3H), 2.47 (t,J=6.3 Hz, 3H), 2.04 (s, 3H), 1.93-1.75 (m, 3H), 1.31-1.15 (m, 2H). MS(ESI) m/z: 1087.5 [M+H]⁺.

Example 109:(2S,4R)-1-((S)-2-(2-(2-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-2-oxoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-045)

CPD-045 was synthesized following the standard procedure for preparingCPD-053 (15 mg, yield 79%). MS (ESI) m/z: 1075.5 [M+H]⁺.

Example 110:(2S,4R)-1-((S)-2-(4-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-1-yl)amino)phenyl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-046)

CPD-046 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 73%). MS (ESI) m/z: 1059.5 [M+H]⁺.

Example 111:(2S,4R)-1-((S)-2-(7-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl-3-((tetrahydro-2H-pyran4-yl)amino)phenyl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-047)

CPD-047 was synthesized following the standard procedure for preparingCPI)-053 (15 mg, yield 78%). MS (ESI) m/z: 1101.5 [M+H]⁺.

Example 112:(2S,4R)-1-((S)-2-(3-(3-(4-(4-((5-(3,5-Difluorobenzyl-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-3-oxopropoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-048)

CPD-048 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 72%). MS (ESI) m/z: 1103.5 [M+H]⁺.

Example 113:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-049)

CPD-049 was synthesized following tide standard procedure for preparingCPD-053 (15 mg, yield 81%). MS (ESI) m/z:930.4 [M+H]⁺.

Example 114:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-050)

CPD-050 was synthesized following the standard procedure for preparingCPD-053 (12 mg, yield 76%). MS (ESI) m/z: 902.4 [M+H]⁺.

Example 115:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-051)

CPD-051 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 72%. ¹H NMR (400 MHz, DMSO-d₆) δ 12.64 (s, 1H),11.09 (s, 1H), 10.11 (s, 1H), 8.29 (s, 1H), 7.82 (s, 1H), 7.60 (d, J=7.8Hz, 1H), 7.49 (s, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H),7.18 (d, H=8.5 Hz, 1H), 7.01 (dd, J=24.2, 7.5 Hz, 4H), 6.24 (d, J=8.8Hz, 1H), 6.13 (s, 1H), 5.04 (d, J=8.3 Hz, 1H), 3.81 (s, 2H), 3.59 (m,8H),3.49 (t, J=10.0 Hz, 3H), 3.29 (s, 4H), 2.86 (d, J=13.9 Hz, 1H), 2.73(s, 2H), 1.94 (d, J=12.9 Hz, 4H), 1.35 (d, J=10.2 Hz, 2H), 1.24 (s, 1H).MS (ESI) m/z: 874.3 1 [M+H]⁺.

Example 116:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-052)

CPD-052 was synthesized following the standard procedure for preparingCPD-053 (14 mg, yield 77%). MS (ESI) m/z: 944.4 [M+H]⁺.

Example 117:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-2H)amino)benzamide(CPD-054)

CPD-054 was synthesized following the standard procedure for preparingCPD-053 (12 mg, yield 73%). MS (ESI) m/z: 1094.5 [M+H]⁺.

Example118:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-055)

CPD-055 was synthesized following the standard procedure for preparingCPD-053 (14 mg, yield 79%). MS (ESI) m/z: 860.3 [M+H]⁺.

Example 119:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanol)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-056)

CPD-056 was synthesized following the standard procedure for preparingCPI)-053 (11 mg, yield 71%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.65 (s,1H),11.10 (s, 1H), 10.12 (s, 1H), 8.30 (s, 1H), 7.82(d, J=9.0 Hz, 1H),7.67-7.54 (m, 1H), 7.49 (s, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.25 (d, J=8.6Hz, 1H), 7.17-6.90 (m, 3H), 6.60 (d, J=42.5 Hz, 1H), 6.25 (d, J=8.4 Hz,1H), 6.14 (s. 1H), 5.33 (d, J=4.8 Hz, 1H), 5.05 (dd, J=12.8, 5.2 Hz,1H), 4.04 (s, 1H) 3.82 (d, J=11.5 Hz, 1H), 3.74-3.44 (m, 5H), 3.26 (dd,J=39.1, 19.2 Hz, 5H), 3.00-2.52 (m, 3H), 2.37(t, J=7.2 Hz, 2H),2.12-1.81(m, 3H), 1.58 (dd, J=14.2, 7.0 Hz, 3H), 1.51-1.08 (m,8H), 0.84(d, J=6.9 Hz, 1H). MS (ESI) m/z: 916.4 [M+H]⁺.

Example 120:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)4-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2,-((tetrahydro-2H-pyran-4-yl)amino)benzamide (CPD-057)

CPD-057 was synthesized following the standard procedure for preparingCPD-053 (14 mg, yield 78%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.75 (d, J=68.8Hz, 1H), 11.09 (s, 1H), 10.20 (d, J=59.5 Hz, 1H), 7.82 (d, J=9.0 Hz,1H), 7.64-7.53 (m, 1H), 7.46 (d, J=17.1 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H),7.29-7.20 (m, 1H), 7.20-7.07 (m, 1H), 6.99 (dt, J=38.9, 17.1 Hz, 3H),6.63 (d, J=20.8 Hz, 1H), 6.24 (d, J=7.8 Hz, 1H), 6.15 (s, 1H), 5.32 (t,J=4.7 Hz, 1H), 5.06 (dd, J=12.9, 5.3 Hz, 1H), 4.04 (s, 2H), 3.89-3.74(m, 2H), 3.72-3.56 (m, 8H), 3.24 (dd, J=28.3, 24.5 Hz, 3H), 2.99-2.81(m, 1H), 2.77 (d, J=4.8 Hz, 1H), 2.70-2.51 (m, 9H).2.11-1.84 (m, 3H),1.53-1.10 (m, 7H), 0.85 (t, J=6.6 Hz, 1H). MS (ESI) m/z: 1006.4 [M+H]⁺.

Example 121:(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methlylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-058)

CPD-058 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 72%). MS (ESI) m/z: 1163.5 [M+H]⁺.

Example 122:N-(2-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-3-yl)piperazin-1-yl)acetamide(CPD-059)

CPD-059 was synthesized following the standard procedure for preparingCPD-053 (14 mg, yield 76%). MS (ESI) m/z: 932.4 [M+H]⁺.

Example 123:N-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-2-(4(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(CPD-060)

CPD-060 was synthesized following the standard procedure for preparingCPD-053 (13 mg, yield 78%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (d, J=8.8Hz, 1H), 10.50 (s, 1H), 8.94 (t, J=5,4 Hz, 1H), 8.51 (s, 1H). 8.13 (d,J=10.9 Hz, 1H), 7.61 (dt, J=13.9, 7.0 Hz, 2H), 7.45-7.35 (m, 1H),7.26-7.12 (m, 3H), 7.05 (t, J=7.2 Hz, 2H), 6.95 (d, J=8.9 Hz, 1H), 6.76(s, 1H), 5.23 (d, J=6.3 Hz. 1H), 5.07 (dd, J=12.8, 5.5 Hz, 1H), 4.47 (s,2H), 4.14-3.93 (m, 4H), 3.72 (dd, J=17.8, 8.2 Hz, 3H), 3.42-3.36 (m,4H), 3.21 (s, 3H), 2.95-2.80 (m, 1H), 2.65-2.53 (m, 2H), 2.04 (dd,J=31.3, 12.8 Hz, 3H), 1.91 (s, 2H), 1.25 (d, J=10.1 Hz, 1H). MS (ESI)m/z: 800.3 [M+H]⁺.

Example 124:(2S,4R)-1-((S)-2-(8-(2-(4-(4-((5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)acetamido)octanamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideCPD-061)

CPD-061 was synthesized following the standard procedure for preparingCPD-053 (10 mg, yield 76%). MS (ESI) m/z: 11.58.6 [M+H]⁺.

Example 125:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)4-(4-(2-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-062)

CPD-062 was synthesized following the standard procedure for preparingCPD-053 (12 mg, yield 72%). MS (ESI) m/z: 903.4 [M+H]⁺.

Example126:(2S,4R)-1-((S)-2-(2-(2-(4-(4-((5-(3,5Difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)acetamido)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(CPD-063)

CPD-063 was synthesized following the standard procedure for preparingCPD-053 (15 mg, yield 76%). MS (ESI) m/z: 1073.5 [M+H]⁺.

Example127:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12-trioxa-3-azatetradecyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-064)

CPD-064 was synthesized following the standard procedure for preparingCPD-053 (11 mg, yield 77%). MS (ESI) m/z: 1035.4 [M+H]⁺.

Example128:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12,15,18-pentaoxa-3-azaicosyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(CPD-065)

CPD-065 was synthesized following the standard procedure for preparingCPD-053 (13 mg, yield 79%). MS (ESI) m/z: 1123.5 [M+H]⁺.

Example 129: 5-((2-(2-Aminoethoxy)ethyl)amino)-2-(2dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 60)

A mixture of 5-fluoroisobenzofuran-1,3-dione (87 g, 524 mmol),3-aminopiperidine-2,6-dione (85.7 g, 524 mmol) and NaOAc (85.9 g, 1050mmol) in acetic acid (500 mL) was stirred at 130° C. overnight. Aftercooling down to room temperature, the mixture was concentrated. Theresulting residue was poured into ice water, and filtered. The filtercake was washed with water (500 mL×2), EtOH (500 mL×2), MeOH (500 mL)and DCM (500 mL) to afford a solid which was dried in vacuum to give2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (120 g, yield:83%) as yellow solid. MS (ESI) m/z=277.1 [M+H]⁺.

A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluouoroisoindoline-1,3-dione(6.9 g, 25.0 mmol), tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (5.6 g,27.5 mmol) and DIEA (9.7 g, 75 mmol) in NMP (75 mL) was stirred at 130°C. in microwave reactor for 50 min. After cooling down to roomtemperature, the mixture was poured into EtOAc (200 mL), and washed withwater (200 mL×2) followed by brine (200 mL). The organic phase was driedover anhydrous Na₂SO₄, filtered and concentrated to give a crude productwhich was purified by silica gel chromatography (petroleumether:EtOAc=2:1 to 1:2) to give tert-butyl(2-(2((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)carbamate (2.4 g, yield: 21%) as yellow oil. MS (ESI) m/z=361.1[M+H]⁺.

To a solution of tert-butyl(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)carbamate(2.4 g, 5.2 mmol) in DCM (10 mL) was added TFA (5 mL) in one portion.The reaction mixture was stirred at room temperature for 2 h. Afterconcentration, the resulting residue was dissolved in water (20 mL),washed with EtOAc (40 mL) and MTBE (40 mL). The aqueous phase waslyophilized to afford TFA salt of5-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.9 g, 77%) as yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.06 (s, 1H), 8.01 (s, 3H), 7.58 (d, J=8.4 Hz, 1H), 7.12(br, s, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.91 (dd, J=2.0 Hz, 8.8 Hz, 1H),5.04 (dd, J=5.6 Hz, 13.2 Hz, 1H),3.64 (t, J=5.6 Hz, 4H),3.40 (t, J=5.2Hz, 2H), 3.01 (br, 2H), 2.89-2.83 (m, 1H), 2.60-2.50 (m, 2H),2.03-1.97(m, 1H). MS (ESI) m/z=361.1 [M+H]⁺.

Example 130:5-((2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 61)

Linker 61 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.4 g, yield: 71%). ¹H NMR (400 MHz, DMSO-d₆)δ 11.05 (s, 1H), 7.94 (br, 3H), 7.56 (d, J=8.4 Hz, 1H), 7.01 (s, 1H),6.90 (d, J=8.0 Hz, 1H), 5.03 (dd, J=5.2 Hz, 12.8 Hz, 1H), 3.58 (br, 8H),3.36 (s, 2H), 2.97-2.92 (m, 2H), 2.91-2.83 (m, 1H), 2.60-2.50 (m, 2H),2.01-1.99 (m, 1H). MS (ESI) m/z=405.1 [M+H]⁺.

Example 131:5-((2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 62)

Linker 62 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.19 g, yield: 59%). ¹H NMR (400 MHz,DMSO-d₆) δ 11.05 (s, 1H), 7.79 (br, 3H), 7.57 (d, J=8.4 Hz, 1H), 7.15(br, s, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.90 (dd, J=2.0 Hz, 8.4 Hz, 1H),5.03 (dd, J=5.6 Hz, 12.8 Hz, 1H), 3.61-3.55 (m, 12H), 3.36 (t, J=5.6 Hz,2H), 2.99-2.94 (m, 2H), 2.88-2.84 (m, 1H), 2,60-2.52 (m, 2H) 2.01-1.98(m, 1H). MS (ESI) m/z=449.1 [M+H]⁺.

Example 132:5-((14-Amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 63)

Linker 63 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.2 g, yield: 73%). ¹H NMR (400 MHz, DMSO-d₆)δ 11.05 (s, 1H), 7.79 (br, J=1.6 Hz, 3H), 7.56 (d, J=8.4 Hz, 1H), 7.14(hr, s, 1H), 7.01 (d, J=2,0 Hz, 1H), 6.90 (dd, J=2.0 Hz, 8.4 Hz, 1H),5.03 (dd, J=5.6 Hz, 13.2 Hz, 1H), 3.61-3.56 (m, 16H), 3.36 (t, J=5.2 Hz,2H), 2.99-2.95 (m, 2H), 2.89-2.83 (m, 1H), 2.60-2.53 (m, 2H) 2.01-1.97(m, 1H). MS (ESI) m/z=493.1 [M+H]⁺.

Example 133:5-((17-Amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-(2,6-dioxopipenidin-3-yl)isoindoline-1,3-dione(Linker 64)

Linker 64 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.73 g, yield: 88%). ¹H NMR (400 MHz,DMSO-d₆) δ 11.05 (s, 1H), 7.79 (s, 3H), 7.55 (d, J=8.4 Hz, 1H), 7.18(hr, s, 1H), 7.01 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 5.03 (dd, J=5.2 Hz,12.8 Hz, 1H),3.61-3.54 (m, 20H), 3.35 (s, 2H), 2.98(s, 2H), 2.92-2,83(m, 1H), 2.61-2.54 (m, 2H), 2.02-1.98 (m, 1H). MS (ESI) m/z=537.2[M+H]⁺.

Example 134:(2-(2.6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycine (Linker65)

Linker 65 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.0 g, yield: 84%). ¹H NMR (400 MHz, DMSO-d₆)δ 12.80 (br, 1H), 11.06 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.32 (br, s,1H), 6.98 (d, J=1.2 Hz, 1H), 6.89 (dd, J=2.0 Hz, 8.4 Hz, 1H), 5.04 (dd,J=5.6 Hz, 13.2 Hz, 1H), 4.03 (s, 2H), 2.92-2.83 (m, 1H), 2.60-2.52 (m,2H), 2.03-1.98 (m, 1H). MS (ESI) m/z=332.0 [M+H]⁺.

Example 135:3-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propanoicacid (Linker 66)

Linker 66 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.24 g, yield: 60%). ¹H NMR (400 MHz,DMSO-d₆) δ 11.05 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 6.97 (d, J=2.0 Hz,1H), 6.87 (dd, J=2.0 Hz, 8.4 Hz, 1H), 5.02 (dd, J=5.2 Hz, 12.8 Hz, 1H),3.41 (t, J=6.8 Hz, 2H), 2.89-2.83 (m, 1H), 2.60-2.52 (m, 4H), 2.02-1.97(m, 1H). MS (ESI) m/z=346.0 [M+H]⁺.

Example 136:4-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butanoicacid (Linker 67)

Linker 67 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (0.52 g, yield: 25%). ¹H NMR (400 MHz,DMSO-d₆) δ 12.12 (s, 1H), 11.05 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.14(t, J=4.8 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 6.85 (dd, J=2.0 Hz, 8.4 Hz,1H), 5.02 (dd, J=5.6 Hz, 12.8 Hz, 1H), 3.21-3.16 (m, 2H), 2.91-2.83 (m,1H), 2.60-2.51 (m, 2H), 2.34 (t, J=7.2 Hz, 2H), 2.01-1.97 (m, 1H),1.82-1.75 (m, 2H). MS (ESI) m/z=360.1 [M+H]⁺.

Example 137:5-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoicacid (Linker 68)

Linker 68 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (0.66 g, 51%). ¹H NMR. (400 MHz, DMSO-d₆) δ12.03 (br, 1H). 11.05 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.10 (t, J=5.2Hz, 1H), 6.94 (s, 1H), 6.83 (dd, J=1.6 Hz, 8.4 Hz, 1H), 5.02 (dd, J=5.6Hz, 12.8 Hz, 1H), 3.17-3.16 (m, 2H), 2.92-2.83 (m, 1H), 2.60-2.53 (m,2H), 2.26-2.25 (m, 2H), 2.01-1.98 (m, 1H), 1.60-1.59 (m, 4H). MS (ESI)m/z=374.1 [M+H]⁺.

Example 138:6-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoicacid (Linker 69)

Linker 69 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.33 g, yield: 66%). ¹H NMR (400 MHz,DMSO-d₆) δ 11.98 (s, 1H), 11.05 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.08(t, J=5.2 Hz, 1H), 6.95 (s, 1H), 6.83 (dd, J=1.2 Hz, 8.4 Hz, 1H), 5.03(dd, J=5.2 Hz, 12.8 Hz, 1H), 3.17-3.12 (m, 2H), 2.92-2.83 (m, 1H),2.60-2.53 (m, 2H), 2.22 (t, J=7.2 Hz, 2H) 2.01-1.98 (m, 1H), 1.61-1.51(m, 4H),1.41-1.33 (m, 2H). MS (ESI) m/z=388.1 [M+H]⁺.

Example 139:7-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptanoicacid (Linker 70)

Linker 70 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.06 g, yield: 39%). ¹H NMR (400 MHz,DMSO-d₆) δ 11.94 (s, 1H), 11.04 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.09(t, J=5.6 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.84 (dd, J=2.0 Hz, 8.4 Hz,1H), 5.02 (dd, J=5.6 Hz, 13.2 Hz, 1H), 3.17-3.12 (m, 2H), 2.88-2.83 (m,1H), 2.60-2.53 (m, 2H), 2.21 (t, J=7.2 Hz, 2H), 2.01-1.97 (m, 1H),1.58-1.48 (m, 4H), 1.39-1.29 (m, 4H). MS (ESI) m/z=402.1 [M+H]⁺.

Example 140:8-((2-(2,6-Dioxopiperdin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoicacid (Linker 71)

Linker 71 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.66 g, yield: 51%). ¹H NMR (400 MHz,DMSO-d₆) δ 11.95 (s, 1H), 11.05 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.09(t, J=5.6 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.84 (dd, J=2.0 Hz, 8.4 Hz,1H), 5.02 (dd, J=5.6 Hz, 13.2 Hz, 1H), 3.17-3.12 (m, 2H), 2.88-2.83 (m,1H), 2.60-2.53 (m, 2H), 2.19 (t, J=7.2 Hz, 2H). 2.02-1.98 (m, 1H),1.58-1.47 (m, 4H), 1.36-1.29 (m, 6H). MS (ESI) m/z=416.1 [M+H]⁺.

Example 141:5-((2-Aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 72)

Linker 72 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.74 g, yield: 80%), ¹H NMR (400 MHz,DMSO-d₆) δ 11.08 (s, 1H), 8.10 (s, 3H), 7.62 (d, J=8.4 Hz, 1H), 7.33 (t,J=5.2 Hz, 1H), 7.05 (s, 1H), 6.94 (d, J=8.0 Hz, 1H), 5.07 (dd, J=5.2 Hz,12.8 Hz, 1H), 3.50-3.49 (m, 2H), 3.03 (t, J=6.0 Hz, 2H), 2.95-2.86 (m,1H),2.63-2.57 (m, 2H), 2.05-2.02 (m, 1H). MS (ESI) m/z=317.1 [M+H]⁺.

Example 142:5-((3-Aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 73)

Linker 73 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.3 g, yield: 57%). ¹H NMR (400 MHz, DMSO-d₆)δ 11.07 (s, 1H), 7.85 (br, 3H), 7.59 (d, J=8.4 Hz, 1H), 7.22 (t, J=5.2Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.88 (dd, J=2.0 Hz, 8.4 Hz, 1H), 5.04(dd, J=5.6 Hz, 13.2 Hz, 1H), 3.29-3.25 (m, 2H), 2.91-2.85 (m, 3H),2.60-2.53 (m, 2H), 2.02-1.98 (m, 1H), 1.87-1.81 (m, 2H). MS (ESI) m/z331.1 [M+H]⁺.

Example 143:5-((4-Aminobutyl)amino)-2-(2,6-(dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 74)

Linker 74 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (2.9 g, yield: 85%). ¹H NMR (400 MHz, DMSO-d₆)δ 11.08 (s, 1H), 7.97 (br, 3H), 7.58 (d, J=8.4 Hz, 1H), 7.22 (br, s,1H), 6.99 (s, 1H), 6.89 (d, J=8.0 Hz, 1H), 5.05 (dd, J=5.2 Hz, 12.8 Hz,1H), 3.22 (s, 2H), 2.93-2.84 (m, 3H), 2.63-2.53 (m, 2H), 2.04-2.00 (m,1H), 1.66 (s, 4H). MS (ESI) m/z=345.1 [M+H]⁺.

Example 144:5-((5-Aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 75)

Linker 75 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.8 g, yield: 78%). ¹H NMR (400 MHz, DMSO-d₆)δ 11.09 (s, 1H), 7.89 (br, 3H), 7.57 (d, J=6.8 Hz, 1H), 7.17 (br, s,1H), 6.96 (s, 1H), 6.86 (d, J=6.0 Hz, 1H), 5.05 (d, J=7.2 Hz, 1J),3.19-3.15 (m, 2H), 2.89-2.70 (m, 3H), 2.61-2.51 (m, 2H) 2.01-1.90 (m,1H), 1.62-1.56 (m, 4H), 1.45-1.40 (m, 2H). MS (ESI) m/z=359.1 [M+H]⁺.

Example 145:5-((6-Aminohexyl)amino)-2-(2,6-dioxopipoidin-3-yl)isoindoline-1,3-dione(Linker 76)

Linker 76 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.8 g, yield: 62%). ¹H NMR (400 MHz, DMSO-d₆)δ 11.05 (s, 1H), 7.71 (br, 3H), 7.57 (d, J=8.4 Hz, 1H), 7.12 (t, J=5.2Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.85 (dd, J=2.0 Hz, 8.4 Hz, 1H), 5.03(dd, J=5.2 Hz, 12.8 Hz, 1H), 3.17-3.16 (m, 2H), 2.88-2.77 (m, 3H),2.60-2.53 (m, 2H), 2.01-1.98 (m, 1H), 1.59-1.51 (m, 4H), 1.37-1.36 (m,4H). MS (ESI) m/z=373.1 [M+H]⁺.

Example 146:5-((7-Aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 77)

Linker 77 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.3 g, yield: 70%). ¹H NMR (400 MHz, DMSO-d₆)δ 11.05 (s, 1H), 7.72 (br, 3H), 7.56 (d, J=8.41 Hz, 1H), 7.12(t, J=5.6Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.85 (dd, J=2.4 Hz, 8.8 Hz, 1H), 5.03(dd, J=5.6 Hz, 12.8 Hz, 1H), 3.18-3.14 (m, 2H), 2.92-2.76 (m, 3H),2.60-2.51 (m, 2H), 2.01-1.98 (m, 1H), 1.59-1.51 (m, 4H), 1.36-1.32 (m,6H). MS (ESI) m/z=387.1 [M+H]⁺.

Example 147:5-((8-Aminonctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Linker 78)

Linker 78 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.6 g, yield: 62%). ¹H NMR (400 MHz, DMSO-d₆)δ 11.05 (s, 1H), 7.73 (br, 3H), 7.56 (d, J=8.4 Hz, 1H), 7.14 (br, 1H),6.94 (d, J=1.61 Hz, 1H), 6.85 (dd, J=2.0 Hz, 8.8 Hz, 1H), 5.03 (dd,J=5.6 Hz, 12.8 Hz, 1H), 3.15 (t, J=7.2 Hz, 2H), 2.89-2.83 (m 1H),2.80-2.75 (m, 2H), 2.60-2.54 (m, 2H). 2.02-1.98 (m, 1H), 1.59-1.51 (m,4H), 1.37-1.30 (m, 8H). MS (ESI) m/z=401.1 [M+H]⁺.

Example 148:3-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoicacid (Linker 79)

Linker 79 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.7 g, yield: 60%). ¹H NMR (400 MHz, DMSO-d₆)δ 12.19 (br, 1H), 11.06 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.09 (br, 1H),7.01 (d, J=2.0 Hz, 1H), 6.90 (dd, J=2.0 Hz, 8.4 Hz, 1H), 5.04 (dd, J=5.6Hz, 13.2 Hz, 1H), 3.66 (t, J=6.4 Hz, 2H), 3.59 (t, J=5.6 Hz, 2H), 3.35(t, J=5.2 Hz, 2H), 2.93-2.84 (m, 1H), 2.62-2.56 (m, 2H), 2.52-2.47 (m,2H), 2.03-1.99 (m, 1H). MS (ESI) m/z=390.1 [M+H]⁺.

Example 149:3-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanoicacid (Linker 80)

Linker 80 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (2.3 g, yield: 78%). ¹H NMR (400 MHz, DMSO-d₆)δ 11.06 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.90(dd, J=2.0 Hz, 8.4 Hz, 1H), 5.04 (dd, J=5.6 Hz, 13.2 Hz, 1H), 3.63-3.59(m, 4H), 3.57-3.51 (m, 4H), 3.36 (t, J=5.6 Hz, 2H), 2.90-2.84 (m, 1H),2.61-2.55 (m, 2H) 2.44 (t, J=6.4 Hz, 2H), 2.04-1.99 (m, 1H). MS (ESI)m/z=434.1 [M+H]⁺.

Example 150:3-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoicacid (Linker 81)

Linker 81 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.2 g, yield: 52%). ¹H NMR (400 MHz, DMSO-d₆)δ 7.59 (d, J=11.2 Hz, 1H), 7.23 (t, J=6.8 Hz, 1H), 7.04 (d, J=1.6 Hz,1H), 7.04 (dd, J=2.4 Hz, 11.2 Hz, 1H), 5.06 (dd, J=7.2 Hz, 16.8 Hz, 1H),3.64-3.57 (m, 8H), 3.54-3.48 (m, 4H), 3.40-3.38 (m, 2H), 2.92-2.89 (m,1H), 2.64-2.54 (m, 2H), 2.42-2.38 (m, 2H), 2.05-2.01 (m, 1H). MS (ESI)m/z=478.1 [M+H]⁺.

Example 151:1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oicacid (Linker 82)

Linker 82 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.3 g, yield: 55%). ¹H NMR (400 MHz, DMSO-d₆)δ 12.17 (br, 1H), 11.07 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.17 (t, J=5.6Hz, 1H), 7.01 (d, J=1.2 Hz, 1H), 6.90 (dd, J=1.6 Hz, 8.4 Hz, 1H), 5.03(dd, J=5.6 Hz, 12.8 Hz, 1H), 3.61-3.48 (m, 18H), 2.92-2.83 (m, 1H),2.60-2.54 (m, 2H), 2.43 (t, J=6.4 Hz, 2H), 2.03-1.98 (m, 1H). MS (ESI)m/z=522.1 [M+H]⁺.

Example 152:1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oicacid (Linker 83)

Linker 83 was synthesized following the same procedure as Linker 60 asdescribed for Example 60. (1.0 g, yield: 50%). ¹H NMR (400 MHz, DMSO-d₆)δ 12.17 (br, s, 1H),11.07 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.17 (t,J=5.6 Hz, 1H), 7.01 (s, 1H), 6.90 (dd, J=1.6 Hz, 8.4 Hz, 1H), 5.03 (dd,J=5.6 Hz, 13.2 Hz, 1H), 3.60-3.48 (m, 22H), 2.89-2,83 (m, 1H), 2.60-2.54(m, 2H), 2.43 (t, J=6.4 Hz, 2H), 2.01-1.98 (m, 1H). MS (ESI) m/z=566.1[M+H]⁺.

Example 153:N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-102)

TR-102 was synthesized following the standard procedure for preparingTR-059 (12 mg, yield 65%). MS (ESI) m/z: 884.7 [M+H]⁺.

Example 154:N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-21)piperazin-1-yl)acetamide (TR-103)

TR-103 was synthesized following the standard procedure for preparingTR-059 (11 mg, yield 63%). MS (ESI) m/z: 842.7 [M+H]⁺.

Example 155:N-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin4-yl)amino)-3,6,9,12,15-pentaoxaheptadecyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-104)

TR-104 was synthesized following the standard procedure for preparingTR-059 (12 mg, yield 60%). MS (ESI) m/z: 1020.9 [M+H]⁺.

Example 156:N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-105)

TR-105 was synthesized following the standard procedure for preparingTR-059 (11 mg, yield 63%). MS (ESI) m/z: 888.8 [M+H]⁺.

Example 157:N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-106)

TR-106 was synthesized following the standard procedure for preparingTR-059 (10 mg, yield 55%). MS (ESI) m/z: 844.6 [M+H]⁺.

Example 158:1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-107)

TR-107 was synthesized following the standard procedure for preparingTR-059 (11.5 mg, yield 62%). MS (ESI) m/z: 828.6 [M+H]⁺.

Example 159:N-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin4-yl)amino)-3,6,9,12-tetraoxatetradecyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-108)

TR-108 was synthesized following the standard procedure for preparingTR-059 (13 mg, yield 64%). MS (ESI) m/z: 976.8 [M+H]⁺.

Example 160:N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-109)

TR-109 was synthesized following the standard procedure for preparingTR-059 (12 mg, yield 63%). MS (ESI) m/z: 814.6 [M+H]⁺.

Example 161:N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-110)

TR-110 was synthesized following the standard procedure for preparingTR-059 (10 mg, yield 61%). MS (ESI) m/z: 870.7 [M+H]⁺.

Example 162:N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-111)

TR-111 was synthesized following the standard procedure for preparingTR-059 (8.6 mg, yield 60%). MS (ESI) m/z: 856.7 [M+H]⁺.

Example 163:2-(2,6-Dioxopiperidin-3-yl)-5-((2-(2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione(TR-113)

TR-113 was synthesized following the standard procedure for preparingTR-053 (7.7 mg, yield 59%). MS (ESI) m/z: 859.8 [M+H]⁺.

Example 164:2-(2,6-Dioxopiperidin-3-yl)-5-((2-(2-(2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione(TR-114)

TR-114 was synthesized following the standard procedure for preparingTR-053 (8.6 mg, yield 61%). MS (ESI) m/z: 903.9 [M+H]⁺.

Example 165:2-(2,6-Dioxopiperidin-3-yl)-5-((5-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione(TR-115)

TR-115 was synthesized following the standard procedure for preparingTR053 (8.1 mg, yield 66%). MS (ESI) m/z: 799.8 [M+H]⁺.

Example 166:2-(2,6-Dioxopiperidin-3-yl)-5-((18-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)isoindoline-13-dione(TR-116)

TR-116 was synthesized following the standard procedure for preparingTR-053 (8.6 mg, yield 64%). MS (ESI) m/z: 991.6 [M+H]⁺.

Example 167:2-(2,6-Dioxopiperidin-3-yl)-5-((7-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione(TR-117)

TR-117 was synthesized following the standard procedure for preparingTR-053 (8.8 mg, yield 61%). MS (ESI) m/z: 827.6 [M+H]⁺.

Example 168:2-(2,6-Dioxopiperidin-3-yl)-5-((2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-8-oxoocetyl)amino)isoindoline-1,3-dione(TR-118)

TR-118 was synthesized following the standard procedure for preparingTR-053 (8.8 mg, yield 61%). MS (ESI) m/z: 841.6 [M+H]⁺.

Example 169:2-(2,6-Dioxopiperidin-3-yl)-5-((2-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)isoindoline-1,3-dione(TR-119)

TR-119 was synthesized following the standard procedure for preparingTR-053 (8.9 mg, yield 61%). MS (ESI) m/z: 815.5 [M+H]⁺.

Example 170:2-(2,6-Dioxopiperidin-3-yl)-5-((15-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapeotadecyl)amino)isoiodoline-1,3-dione(TR-120)

TR-120 was synthesized following the standard procedure for preparingTR-053 (8.9 mg, yield 61%). MS (ESI) m/z: 947.6 [M+H]⁺.

Example 171:2-(2,6-Dioxopiperidin-3-yl)-5-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione(TR-121)

TR-121 was synthesized following the standard procedure for preparingTR-053 (10.6 mg, yield 63%). MS (ESI) m/z: 1542.5 [M+H]⁺.

Example 172:2-(2,6-Dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-6-oxohexyl)amino)isoindoline-1,3-dione(TR-122)

TR-122 was synthesized following the standard procedure for preparingTR-053 (10.6 mg, yield 62%). MS (ESI) m/z: 813.9 [M+H]⁺.

Example 173:2-(2,6-Dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione(TR-123)

TR-123 was synthesized following the standard procedure for preparingTR-053 (10.6 mg, yield 62%). MS (ESI) m/z: 1514.8 [M+H]⁺.

Example 174:N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-124)

TR-124 was synthesized following the standard procedure for preparingTR-059 (9.3 mg, yield 61%). MS (ESI) m/z: 828.5 [M+H]⁺.

Example 175:N-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12-tetraoxatetradecyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-125)

TR-125 was synthesized following the standard procedure for preparingTR-059 (9.6 mg, yield 62%). MS (ESI) m/z: 976.8 [M+H]⁺.

Example 176:N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-126)

TR-126 was synthesized following the standard procedure for preparingTR-059 (9.9 mg, yield 63%). MS (ESI) m/z: 870.7 [M+H]⁺.

Example 177:N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-127)

TR-127 was synthesized following the standard procedure for preparingTR-059 (9.3 mg, yield 61%). MS (ESI) m/z: 814.6 [M+H]⁺.

Example 178:N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-128)

TR-128 was synthesized following the standard procedure for preparingTR-059 (9.7 mg, yield 62%). MS (ESI) m/z: 856.7 [M+H]⁺.

Example 179:N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imittlazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide (TR-129)

TR-129 was synthesized following the standard procedure for preparingTR-059 (9.71 mg, yield 62%). MS (ESI) m.z: 932.6 [M+H]⁺.

Example 180:N-(2((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-130)

TR-130 was synthesized following the standard procedure for preparingTR-059 (9.3 mg, yield 62%). MS (ESI) m/z: 500.5 [M+H]⁺.

Example 181:N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2yl)piperazin-1-yl)acetamide(TR-131)

TR-131 was synthesized following the standard procedure for preparingTR-059 (10.5 mg, yield 65%). MS (ESI) m/z: 842.6 [M+H]⁺.

Example 182:N-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12,15-pentaoxaheptadecyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-132)

TR-132 was synthesized following the standard procedure for preparingTR-059 (7.5 mg, yield 55%). MS (ESI) m/z: 1020.9 [M+H]⁺.

Example 183:N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-133)

TR-133 was synthesized following the standard procedure for preparingTR-059 (8.6 mg, yield 55%). MS (ESI) m/z: 884.7 [M+H]⁺.

Example 184:N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-134)

TR-134 was synthesized following the standard procedure for preparingTR-059 (8.8 mg, yield 59%). MS (ESI) m/z: 888.7 [M+H]⁺.

Example 185:N-(2-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-135)

TR-135 was synthesized following the standard procedure for preparingTR-059 (8.1 mg, yield 56%). MS (ESI) m/z: 844.7 [M+H]⁺.

Example 186:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-136)

TR-136 was synthesized following the standard procedure for preparingTR-053 (11 mg, yield 59%). MS (ESI) m/z: 944.4 [M+H]⁺.

Example 187:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(4((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-137)

TR-137 was synthesized following the standard procedure for preparingTR-053 (13 mg, yield 64%). MS (ESI) m/z: 1094.5 [M+H]⁺.

Example 188:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-138)

TR-138 was synthesized following the standard procedure for preparingTR-053 (14 mg, yield 55%). MS (ESI) m/z: 916.4 [M+H]⁺.

Example 189:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-139)

TR-139 was synthesized following the standard procedure for preparingTR-053 (16 mg, yield 62%). MS (ESI) m/z: 930.4 [M+H]⁺.

Example 190:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-140)

TR-140 was synthesized following the standard procedure for preparingTR-053 (12 mg, yield 56%). MS (ESI) m/z: 1050.4 [M+H]⁺.

Example 191:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-141)

TR-141 was synthesized following the standard procedure for preparingTR-053 (15 mg, yield 65%). MS (ESI) m/z: 962.4 [M+H]⁺.

Example 192:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-142)

TR-142 was synthesized following the standard procedure for preparingTR-053 (12 mg, yield 62%). MS (ESI) m/z: 902.4 [M+H]⁺.

Example 193:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(8-((2-(2,6-dioxopiperidin-3-)-1,3-dioxpisoindolin-5-yl)amino)octanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-143)

TR-143 was synthesized following the standard procedure for preparingTR-053 (16 mg, yield 67%). MS (ESI) m/z: 918.4 [M+H]⁺.

Example 194:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-144)

TR-144 was synthesized following the standard procedure for preparingTR-053 (14 mg, yield 61%). MS (ESI) m/z: 860.3 [M+H]⁺.

Example 195:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-145)

TR-145 was synthesized following the standard procedure for preparingTR-053 (15 mg, yield 62%). MS (ESI) m/z: 874.3 [M+H]⁺.

Example 196:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-146)

TR-146 was synthesized following the standard procedure for preparingTR-053 (16 mg, yield 65%). MS (ESI) m/z: 1006.4 [M+H]⁺.

Example 197:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-147)

TR-147 was synthesized following the standard procedure for preparingTR-053 (12 mg, yield 56%). MS (ESI) m/z: 959.4 [M+H]⁺.

Example 198:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-148)

TR-148 was synthesized following the standard procedure for preparingTR-053 (16 mg, yield 62%). MS (ESI) m/z: 987.5 [M+H]⁺.

Example 199:N-(5-(3,5-Difluorbenzyl)-1H-indazol-3-yl)-4-(4-(2-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-149)

TR-149 was synthesized following the standard procedure for preparingTR-053 (14 mg, yield 52%). MS (ESI) m/z: 945.4 [M+H]⁺.

Example 200:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-150)

TR-150 was synthesized following the standard procedure for preparingTR-053 (14 mg, yield 58%). MS (ESI) m/z: 1079.5 [M+H]⁺.

Example 201:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-151)

TR-151 was synthesized following the standard procedure for preparingTR-053 (12 mg, yield 53%). MS (ESI) m/z: 947.4 [M+H]⁺.

Example 202:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-152)

TR-152 was synthesized following the standard procedure for preparingTR-053 (13 mg, yield 57%). MS (ESI) m/z: 917.4 [M+H]⁺.

Example 203:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-153)

TR-153 was synthesized following the standard procedure for preparingTR-053 (12 mg, yield 53%). MS (ESI) m/z: 991.4 [M+H]⁺.

Example 204:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-154)

TR-154 was synthesized following the standard procedure for preparingTR-053 (15 mg, yield 57%). MS (ESI) m/z: 973.4 [M+H]⁺.

Example 205:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-155)

TR-155 was synthesized following the standard procedure for preparingTR-053 (13 mg, yield 56%). MS (ESI) m/z: 931.4 [M+H]⁺.

Example 206:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-156)

TR-156 was synthesized following the standard procedure for preparingTR-053 (12 mg, yield 53%). MS (ESI) m/z: 931.4 [M+H]⁺.

Example 207:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-157)

TR-157 was synthesized following the standard procedure for preparingTR-053 (14 mg, yield 62%). MS (ESI) m/z: 973.4 [M+H]⁺.

Example 208:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-158)

TR-158 was synthesized following the standard procedure for preparingTR-053 (12 mg, yield 56%). MS (ESI) m/z: 944.4 [M+H]⁺.

Example 209:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-159)

TR-159 was synthesized following the standard procedure for preparingTR-053 (14 mg, yield 58%). MS (ESI) m/z: 987.5 [M+H]⁺.

Example 210:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-160)

TR-160 was synthesized following the standard procedure for preparingTR-053 (13 mg, yield 56%). MS (ESI) m/z: 987.5 [M+H]⁺.

Example 211:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-161)

TR-161 was synthesized following the standard procedure for preparingTR-053 (13 mg, yield 58%). MS (ESI) m/z: 947.4 [M+H]⁺.

Example 212:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-162)

TR-162 was synthesized following the standard procedure for preparingTR-053 (11 mg, yield 52%). MS (ESI) m/z: 9881.4 [M+H]⁺.

Example 213:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxo-6,9,12-trioxa-3-azatetradecyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-163)

TR-163 was synthesized following the standard procedure for preparingTR-053 (15 mg, yield 58%). MS (ESI) m/z: 1035.4 [M+H]⁺.

Example 214:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-164)

TR-164 was synthesized following the standard procedure for preparingTR-053 (13 mg, yield 56%). MS (ESI) m/z: 945.4 [M+H]⁺.

Example 215:N-(5-(3,5-Diflourobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-165)

TR-165 was synthesized following the standard procedure for preparingTR-053 (12 mg, yield 53%). MS (ESI) m/z: 903.4 [M+H]⁺.

Example 216:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxo-6,9,12,15,18-pentaoxa-3-azaicosyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-166)

TR-166 was synthesized following the standard procedure for preparingTR-053 (14 mg, yield 56%). MS (ESI) m/z: 1223.5 [M+H]⁺.

Example 217:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-167)

1 0

TR-167 was synthesized following the standard procedure for preparingTR-053 (14 mg, yield 55%). MS (ESI) m/z: 917.4 [M+H]⁺.

Example 218:2-(2,6-Dioxopiperidin-3-yl)-5-((4-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4-oxobutyl)amino)isoindoline-1,3-dione(TR-168)

TR-168 was synthesized following the standard procedure for preparingTR-053 (16 mg, yield 58%). MS (ESI) m/z: 785.3 [M+H]⁺.

Example 219:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-169)

TR-169 was synthesized following, the standard procedure for preparingTR-053 (14 mg, yield 56%). MS (ESI) m/z: 888.4 [M+H]⁺.

Example 220:2-(2,6-Dioxopiperidin-3-yl)-5-(4-(6(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)isoindoline-1,3-dione(TR-170)

A mixture of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridine-2-yl)imidazo[1,2-b]pyridazine(30 mg, 0.06 mmol),2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (15.8 mg, 0.06mmol), DIEA (0.037 mL, 0.23 mmol) and NMP (0.5 mL) was heated to 120° C.under microwave for 1.5 h. The reaction mixture was purified by reversephase chromatography to give the desired product (8.6 mg, 32% yield) asa light yellow solid. MS (ESI) m/z: 700.3 [M+H]⁺.

Example 221:2-(2,6-Dioxopiperidin-3-yl)-5-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)amino)isoindoline-1,3-dione(TR-171)

Step 1. Synthesis of tert-butyl(R)-(3-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazi[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)carbamate

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.11 mmol) in DMAC (5 mL)were added Na₂CO₃ (24 mg, 0.22 mmol) and tert-butyl(3-bromopropyl)carbamate (39 mg, 0.16 mmol), the resulting mixture wasstirred at 80° C. for 8 h. The reaction was cooled to room temperatureand H₂O (50 mL) was added. The mixture was extracted with EtOAc (10mL×3), the combined organic layers were concentrated and the residue waspurified by reverse phase chromatography to the desired product (43 mg,65% yield) as a pale brown solid. MS (ESI) m/z: 601.3 [M+H]⁺.

Step 2. Synthesis of(R)-3-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propan-1-aminehydrochloride

To a solution tert-butyl(R)-(3-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)carbamate(40 mg, 0.07 mmol) in methanol (2 mL) was added HCl/dioxane (4 M, 2 mL)at room temperature, then it was stirred at room temperature for 5 h.The mixture was concentrated to get the crude product (35 mg, 98% yield)as a pale brown solid which was used directly in the next step. MS (ESI)m/z: 501.3 [M+H]⁺.

Step 3. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)amino)isoindoline-1,3-dione(TR-171)

A mixture of(R)-3-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazol[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propan-1-aminehydrochloride (35 mg, 0.07 mmol),2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (15.8 mg, 0.06mmol), DIEA (0.037 mL, 0.23 mmol) and NMP (0.5 mL) was heated to 120° C.under microwave for 1 h. The reaction mixture was purified by reversephase chromatography to give the desired product (11.2 mg, 22% yield) asa light yellow solid. MS (ESI) m/z: 757.3 [M+H]⁺.

Example 222:2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)isoindoline-1,3-dione(TR-172)

Step 1. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(3-hydroxyprop-1-yn-1-yl)isoindoline-3-dione

A mixture of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(100 mg, 0.30 mmol), prop-2-yn-1-ol (25 mg, 0.45 mmol), Pd(dppf)Cl₂ (22mg, 0.03 mmol), Cul (5.7 mg, 0.03 mmol) and DIPEA (77 mg, 0.60 mmol) inTHF (10 mL) was stirred at reflux for 8 h. The reaction mixture wasconcentrated and the residue was purified by reverse phasechromatography to give the desired product (68 mg, 72% yield) as a palebrown solid. MS (ESI) m/z: 313.3 [M+H]⁺.

Step 2. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(3-hydroxypropyl)isoindoline-1,3-dione

A mixture of2-(2,6-dioxopiperidin-3-yl)-5-(3-hydroxyprop-1-yn-1-yl)isoindoline-1,3-dione(68 mg, 0.22 mmol) and Pd/C (10 mg) in methanol (5 mL) was stirred underH₂ (1 atm, balloon) at room temperature for 5 h. The reaction mixturewas purified by reverse phase chromatography to give the desired product(55 mg, 81% yield) as a light yellow solid. MS (ESI) m/z: 317.1 [M+H]⁺.

Step 3. Synthesis of3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propyl4-methylbenzenesulfonate

To a solution2-(2,6-dioxopiperidin-3-yl)-5-(3-hydroxypropyl)isoindoline-1,3-dione,

(55 mg, 0.17 mmol) and TEA (35 mg, 0.34 mmol) in DCM (5 mL) was added4-methylbenzenesulfonyl chloride (39 mg, 0.20 mmol) at room temperature,then it was stirred at room temperature for 4 h. The mixture wasconcentrated and purified by reverse phase chromatography to give thedesired product (42 mg, 52% yield) as a light yellow solid. MS (ESI)m/z: 471.1 [M+H]⁺.

Step 4. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazol[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)isoindoline-1,3-dione

A mixture of3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propyl4-methylbenzenesulfonate(40 mg, 0.08 mmol),(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(37 mg, 0.08 mmol), K₂CO₃ (22 mg 0.16 mmol) and NaI (1.5 mg, 0.01 mmol)in CH₃CN (3 mL) were stirred at 80° C. for 5 h. LCMS showed the reactionwas completed. The mixture was concentrated and purified by reversephase chromatography to give the desired product (21 mg, 36% yield) as alight yellow solid. MS (ESI) m/z: 742.3 [M+H]⁺.

Example 223:2-(2,6-Dioxopiperidin-3-yl)-5-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[4,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)isoindoline-1,3-dione(TR-173)

Step 1. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(2-hydroxyethoxy)isoindoline-1,3-dione

A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione(1 g, 3.65 mmol), 2-bromoethan-1-ol (452 mg, 3.65 mmol), NaHCO₃ (613 mg,7.30 mmol) and KI (605 mg, 3.65 mmol) in DMF (20 mL) were stirred at100° C. for 16 h. The mixture was filtered and purified by reverse phasechromatography to give the desired product (340 mg, 29% yield) as alight yellow solid. MS (ESI) m/z: 319.1 [M+H]⁺.

Step 3. Synthesis of2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl-4-methylbenzenesulfonate

To a solution2-(2,6-dioxopiperidin-3-yl)-5-(2-hydroxyethoxy)isoindoline-1,3-dione

(200 mg, 0.63 mmol) and TEA (1.26 g, 1,26 mmol) in DCM (15 mL) was added4-methylbenzenesulfonyl chloride (143 mg, 0.76 mmol) at roomtemperature, then it was stirred at room temperature for 4 h. Themixture was concentrated and purified by reverse phase chromatography togive the desired product (172 mg, 58% yield) as a light yellow solid. MS(ESI) m/z: 473.1 [M+H]⁺.

Step 4. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)isoindoline-1,3-dione

A mixture of2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl4-methylbenzenesulfonate (40 mg, 0.08 mmol).(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(37 mg, 0.08 mmol), K₂CO₃ (22 mg, 0.16 mmol) and NaI (1.5 mg, 0.01 mmol)in CH₃CN (3 mL) were stirred at 80° C., for 5 h. LCMS showed thereaction was completed. The mixture was concentrated and purified byreverse phase chromatography to give the desired product (16 mg, 42%yield) as a light yellow solid. MS (ESI) m/z: 744.3 [M+H]⁺.

Example 224: Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)amino)isoindoline-1,3-dione(TR-174)

TR-174 was synthesized following the standard procedure for preparingTR-175. MS (ESI) m/z: 714.3 1 [M+H]⁺.

Example 225:2-(2,6-Dioxopiperidin-3-yl)-5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)isoindoline-1,3-dione(TR-175)

Step 1. Synthesis of tert-butyl3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)azetidine-1-carboxylate

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (200 mg, 724.6umol) in DMSO (3 mL) were added KF (126 mg, 2.17 mmol) andtert-butyl3-aminoazetidine-1-carboxylat (373.9 mg, 2.17 mmol). Theresulting mixture was stirred at 130° C. for 1 hr. After the Imide wastotally consumed, the reaction was poured into water (20 mL) andextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with saturated brine (20 mL), dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure. The resultingresidue was purified by silica gel column chromatography to afford thedesired producttert-butyl3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)azetidine-1-carboxylate(80 mg, 26% yield) as a light yellow solid. MS (ESI) m/z: 429.2 [M+H]⁺.

Step 2. Synthesis of5-(azetidin-3-ylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of tert-butyl3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)azetidine-1-carboxylate(80 mg, 186.9 umol) in DCM (2 mL) was added TFA (2 mL). The resultingmixture was stirred at 25° C. for 5 hr. After the starting material wastotally consumed, the reaction was evaporated under reduced pressure.The resulting residue was purified by reverse-phase chromatography toyield the desired product5-(azetidin-3-ylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(56 mg, 91% yield) as a light yellow solid. MS (ESI) m/z: 329.2 [M+H]⁺.

Step 3. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)isoindoline-1,3-dione

To a solution of5-(azetidin-3-ylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(50 mg, 152.4 umol) in DMSO (3 mL) were added KF (26.5 mg, 457.3 umol)and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine(57.4 mg, 152.4 umol), The resulting mixture was stirred at 130° C. for1 hr. After the Imide was totally consumed, the reaction was poured intowater (20 mL) and extracted with ethyl acetate (3×10 mL). The combinedorganic layers were washed with saturated brine (20 mL), dried overanhydrous sodium sulfate, filtered and evaporated under reducedpressure. The resulting residue was purified by reverse -phasechromatography to afford the desired product2-(2,6-dioxopiperidin-3-yl)-5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)isoindoline-1,3-dione(10 mg,10% yield) as a light yellow solid. MS (ESI) m/z: 686.3 [M+H]⁺.

Example 226: Synthesis of2-(2,6-Dioxopiperidin-3-yl)-5-((2-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridazin-2-yl)piperazin-1-yl)ethoxy)ethyl)amino)isoindoline-1,3-dione(TR-176)

TR-176 was synthesized following the standard procedure for preparingTR-177. MS (ESI) m/z: 787.3 [M+H]⁺.

Example 227: Synthesis of2-(2,6-Dioxopiperidin-3-yl)-5-((2-(2-(2-(4-(6-(6-((S)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione(TR-177)

Step 1. Synthesis of2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl4-methylbenzenesulfonate

To a solution of tert-butyl(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (200 mg, 803.2 umol) inDCM (5 mL) were added DMAP (9.7 mg, 80.3 umol), DIPEA (311 mg, 2.4 mmol)and T_(s)Cl (183.7 mg, 963.8 mmol). The resulting mixture was stirred at25° C. for 15 hr. The reaction was poured into water (20 mL) andextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with saturated brine (20 mL), dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure. The resultingresidue was purified by reverse-phase chromatography to afford thedesired product2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl4-methylbenzenesulfonate(230 mg, 71.2% yield) as a light yellow solid. MS (ESI) m/z: 404.2[M+H]⁺.

Step 2. Synthesis of tert-butyl(S)-(2-(2-(2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethyl)carbamate

To a solution of(S)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(50 mg, 112.8 umol) in CH₃CN (5 mL) were added K2CO3 (46.7 mg, 338.6umol) and NaI (1.5 mg, 11.2 mmol). The resulting mixture was stirred at80° C. for 15 hr. The reaction was poured into water (2.0 mL) andextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with saturated brine (20 mL), dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure. The resultingresidue was purified by reverse-phase chromatography to afford thedesired product tert-butyl(S)-(2-(2-(2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethyl)carbamate(30 mg, 39.6% yield) as a light yellow solid. MS (ESI) m/z: 675.4[M+H]⁺.

Step 3. Synthesis of(S)-2-(2-(2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethan-1-amine

To a solution oftert-butyl(S)-(2-(2-(2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethoxyl)ethyl)carbamate(20 mg, 29.6 umol) in DCM (2 mL) was added TFA (2 mL). The resultingmixture was stirred at 25° C. for 5 hr. After the starting material wastotally consumed, the reaction was evaporated under reduced pressure.The resulting residue was purified by reverse-phase chromatography toyield the desired product(S)-2-(2-(2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethan-1-amine(15 mg, 88% yield) as a light yellow solid. MS (ESI) m/z: 575.3 [M+H]⁺.

Step 4. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-((2-(2-(2-(4-(6-(6-((S)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione(TR-177)

To a solution of tert-butyl(S)-2-(2-(2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethan-1-amine(20 mg, 34.9 umol) NMP (1 mL) were added2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (28.9 mg,104.7 umol) and DIPEA (13 mg, 104.7 umol). Microwave reaction wasstirred at 120° C. for 50 min. The resulting residue was purified byreverse-phase chromatography to yield the desired product2-(2,6-dioxopiperidin-3-yl)-5-((2-(2-(2-(4-(6-(6-((S)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione(10mg, 34.6% yield) as a light yellow solid. MS (ESI) m/z: 831.4 1 [M+H]⁺.

Example 228: Synthesis of2-(2,6-Dioxopiperidin-3-yl)5-(((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)amino)isoindoline-1,3-dione(TR-178)

TR-178 was synthesized following the standard procedure for preparingTR-175. MS (ESI) m/z: 728.3 [M+H]⁺.

Example 229: Synthesis of2-(2,6-Dioxopiperidin-3-yl)-5-(((1(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1)yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)methyl)amino)isoindoline-1,3-dione(TR-179)

TR-179 was synthesized following the standard procedure for preparingTR-175. MS (ESI) m/z: 700.3 [M+H]⁺.

Example 230: Synthesis of2(2,6-Dioxopiperidin-3-yl)-5-((2-(1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)ethyl)amino)isoindoline-1,3-dione(TR-180)

TR-180 was synthesized following the standard procedure for preparingTR-175. MS (ESI) m/z: 742.3 [M+H]⁺.

Example 231:2-(2,6-Dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)isoindoline-1,3-dione(TR-181)

Step 1. Synthesis of tert-butyl(R)-(2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)carbamate

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazinehydrochloride (200 mg, 0.42 mmol) in DMAC (5 mL) were added Na₂CO₃(133.56 mg, 1.26 mmol), NaI (126 mg, 0.84 mmol) and tert-butyl(2-bromoethyl)carbamate (186 mg, 0.83 mmol), the resulting mixture wasstirred at 60° C. for 3 h. The reaction was cooled to room temperatureand H₂O (20 mL) was added. The mixture was extracted with EtOAc (10mL*3), the combined organic layers were concentrated and the residue waspurified by reverse phase chromatography to desired product (225mg, 91%yield) as a white solid. MS (ESI) m/z: 587.9 [M+H]⁺.

Step 2. Synthesis of(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-amine

To a solution tert-butyl(R)-(2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)carbamate(225 mg, 0.38 mmol) in methanol (5 mL) was added HCl/dioxone (4 M, 4 mL)at room temperature, then it was stirred at room temperature for 12 h.The mixture was concentrated to get crude product (220 mg, 99% yield) asa white solid which was used directly in the next step. MS (ESI) m/z:487.7 [M+H]⁺.

Step 3. Synthesis of2-(2,6-Dioxopiperidin-3-yl)-5-((2-(4-(6-(6-((R)-2-(3-fluorophenl)-)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)isoindoline-1,3-dione(TR-181)

A mixture of(R)-2-(4-(6-(6(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-amine(30 mg, 0.06 mmol),2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (15.8 mg, 0.06mmol), DIEA (0.037 mL, 0.23 mmol) and NMP (0.3 mL) was heated to 120° C.under microwave for 2 h. The reaction mixture was purified by reversephase chromatography to give desired product (6.5 mg, 15% yield) as awhite solid. MS (ESI) m/z: 743.8 [M+H]⁺.

Example 232:2-(2,6-Dioxopiperidin-3-yl)-5-(4-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)piperidin-1-yl)isoindoline-1,3-dione(TR-182)

Step 1. Synthesis of tert-butyl(R)-4-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)piperidine-1-carboxylate

The mixture of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(0.050 g, 112.73 umol), tert-butyl4-oxopiperidine-1-carboxylate (44.92mg, 225.47 umol) and AcOH (one drop) in DCE (3 mL) was stirred for 1 h.Then it was added NaBH₃CN (22.62 mg, 338.20 umol) and stirred foranother 16 h. The solvent was removed under vacuum to give the crudeproduct, which was purified by Prep-TLC (MeOH/DCM=5/100) to give thedesired product (8 mg, 11% yield) as a yellow oil. MS (ESI) m/z: 627.8[M+H]⁺.

Step 2. Synthesis of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(4-(piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine

To a solution of tert-butyl(R)-4-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)piperidine-1-carboxylate(8 mg, 12.76 umol) in DCM (5 mL) was added TFA (14.55 mg, 127.64 umol),then the reaction was stirred for 2 h. LCMS showed the reaction wascompleted. The solvent was removed under vacuum to give the crudeproduct (6.72 mg, 99% yield) which was used for next step withoutfurther purification. MS (ESI) m/z: 527.6 [M+H]⁺.

Step 3. Synthesis of2-(2,6-Dioxopiperidin-3-yl)-5-(4-(4-(6-(6-((R)2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-pyridin-2-yl)piperazin-1-yl)piperidin-1-yl)isoindoline-1,3-dione(TR-182)

The mixture of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(4-(piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(6.72 mg, 11.39 umol),2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (3.15 mg, 11.39umol) and DIEA (2.94 mg, 22.79 umol) in NMP (0.5 mL) were heated at 120°C. for 0.5 h under microwave. The mixture was purified by Prep-TLC(DCM/MeOH=100/5) to give the desired product (1.8 mg, 20% yield) as awhite solid. MS (ESI) m/z: 783.8 [M+H]⁺.

Example 233:2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione(TR-183)

Step 1. Synthesis of3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)prop-2-yn-1-yl4-methylbenzenesulfonate

To a solution2-(2,6-dioxopiperidin-3-yl)-5-(3-hydroxyprop-1-yn-1-yl)isoindoline-1,3-dione(50 mg, 0.16 mmol) and TEA (32 mg, 0.32 mmol) in DCM (3 mL) was added4-methylbenzenesulfonyl chloride (36 mg, 0.19 mmol) at room temperature,then it was stirred at room temperature for 4 h. The mixture wasconcentrated and purified by reverse phase chromatography to give thedesired product (43 mg, 58% yield) as a light yellow solid. MS (ESI)m/z: 467.1 [M+H]⁺.

Step 2. Synthesis of2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)iosindoline-1,3-dione

A mixture of3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)prop-2-yn-1-yl4-methylbenzenesulfonate(40 mg, 0.08 mmol),(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(37 mg, 0.08 mmol), K₂CO₃ (22 mg, 0.1.6 mmol) and NaI (1.5 mg, 0.01mmol) in CH₃CN (3 mL) were stirred at 80° C. for 5 h. LCMS showed thereaction was completed. The mixture was concentrated and purified byreverse phase chromatography to give the desired product (18 mg, 28%yield) as a light yellow solid. MS (ESI) m/z 738.3 [M+H]⁺.

Example 234:2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione(TR-184)

Step 1. Synthesis of tert-butyl(R)-3-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidine-1-carboxylate

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(50 mg, 112.73 umol) and tert-butyl 3-oxoazetidine-1-carboxylate (38.60mg, 225.47 nmol) in MeOH (1 mL) AcOH (1 mL) and DCE (2 mL) was addedNaBH₃CN (14.20 mg, 225.47 umol) at room temperature. The resultingreaction mixture was stirred at room temperature for 48 h, concentratedand purified by silica gel chromatography (DCM/MeOH=30/1) to givedesired product (40 mg, 74% yield) as a yellow oil. MS (ESI) m/z: 599.6[M+H]⁺.

Step 2. Synthesis of(R)-3-(6-(4-(azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine

To a solution of tert-butyl(R)-3-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidine-1-carboxylate(60 mg, 100.22 umol) in DCM (2 mL) rests added TFA (228.53 mg, 2.00mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 2 h, and then it was concentrated. The residue wasdissolved in DCM (10 mL), washed with Na₂CO₃(aq), dried over Na₂SO₄,concentrated to give desired product (50 mg, 99 % yield) as a yellowresin. MS (ESI) m/z: 499.5 [M+H]⁺.

Step 3. Synthesis of2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)isoindoline-1,3dione(TR-184)

To a solution of(R)-3-(6-(4-(azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine(50 mg, 100.28 umol) and2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (27.70 mg,100.28 umol) in DMSO (2 mL) was added DIEA (38.81 mg, 300.84 umol) atroom temperature. The reaction mixture was warmed to 110° C. and stirredfor 5 h. After cooling to room temperature, the reaction mixture waspurified by prep-HPLC to give desired product (60 mg, 79% yield) as ayellow solid. MS (ESI) m/z: 755.7 [M+H]⁺.

Example 235:3-(6-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-185)

Step 1. Synthesis of3-(6-(3-hydroxypropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

A mixture of3-(6-(3-hydroxyprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.34 mmol) and Pd/C (20 mg) in methanol (5 mL) was stirredunder H₂ (1 atm, balloon) at room temperature for 3 h. The reactionmixture was purified by reverse phase chromatography to give the desiredproduct (86 mg, 86% yield) as a light yellow solid. MS (ESI) m/z: 303.1[M+H]⁺.

Step 2. Synthesis of3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)propyl4-methylbenzenesulfonate

To a solution3-(6-(3-hydroxypropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (80 mg,0.26 mmol) and TEA (52 mg, 0.52 mmol) in DCM (5 mL) was added4-methylbenzenesulfonyl chloride (59 mg, 0.31 mmol) at room temperature,then it was stirred at room temperature for 2 h. The mixture wasconcentrated and purified by reverse phase chromatography to give thedesired product (61 mg, 51% yield) as a light yellow solid. MS (ESI)m/z: 457.1 [M+H]⁺.

Step 3. Synthesis of3-(6-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

A mixture of3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)propyl4-methylbenzenesulfonate(40 mg, 0.08 mmol),(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(37 mg, 0.08 mmol), K₂CO₃ (22 mg, 0.16 mmol) and NaI (1.5 mg, 0.01 mmol)in CH₃CN (3 mL) were stirred at 80° C. for 5 h. LCMS showed the reactionwas completed. The mixture was concentrated and purified by reversephase chromatography to give the desired product (23 mg, 36% yield) as alight yellow solid. MS (ESI) m/z: 728.3 [M+H]⁺.

Example 236:3-(5-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-186)

Step 1. Synthesis of3-(5-(3-hydroxypropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

A mixture of3-(5-(3-hydroxyprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.34 mmol) and Pd/C (20 mg) in methanol (5 mL) was stirredunder H₂ (1 atm, balloon) at room temperature for 3 h. The reactionmixture was purified by reverse phase chromatography to give the desiredproduct (78 mg, 78% yield) as a light yellow solid. MS (ESI) m/z: 303.1[M+H]⁺.

Step 2. Synthesis of3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)propyl4-methylbenzenesulfonate

To a solution3-(5-(3-hydroxypropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (80 mg,0.26 mmol) and TEA (52 mg, 0.52 mmol) in DCM (5 mL) was added4-methylbenzenesulfonyl chloride (59 mg, 0.31 mmol) at room temperature,then it was stirred at room temperature for 2 h. The mixture wasconcentrated and purified by reverse phase chromatography to give thedesired product (67 mg, 54% yield) as a light yellow solid. MS (ESI)m/z: 457.1 [M+H]⁺.

Step 3. Synthesis of3-(5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1.2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

A mixture of3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)propyl4-methylbenzenesulfonate(40 mg, 0.08 mmol),(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(37 mg, 0.08 mmol), K₂CO₃ (22 mg, 0.16 mmol) and NaI (1.5 mg, 0.01 mmol)in CH₃CN (3 mL) were stirred at 80° C. for 5 h. LCMS showed the reactionwas completed. The mixture was concentrated and purified by reversephase chromatography to give the desired product (26 mg, 38% yield) as alight yellow solid. MS (ESI) m/z: 728.3 [M+H]⁺.

Example 237:2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione(TR-187)

Step 1. Synthesis of3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)prop-2-yn-1-yl4-methylbenzenesulfonate

To a solution3-(6-(3-hydroxyprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(75 mg, 0.26 mmol) and TEA (52 mg, 0.52 mmol) in DCM (5 mL) was added4-methylbenzenesulfonyl chloride (59 mg, 0.31 mmol) at room temperature,then it was stirred at room temperature for 2 h. The mixture wasconcentrated and purified by reverse phase chromatography to give thedesired product (54 mg, 46% yield) as a light yellow solid. MS (ESI)m/z: 453.1 [M+H]⁺.

Step 2. Synthesis of3-(6-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

A mixture of3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)prop-2-yn-1-yl4-methylbenzenesulfonate(40 mg, 0.08 mmol),(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(37 mg, 0.08 mmol), K₂CO₃ (22 mg, 0.16 mmol) and NaI (1.5 mg, 0.01 mmol)in CH₃CN (3 mL) were stirred at 80° C. for 5 h. LCMS showed the reactionwas completed. The mixture was concentrated and purified by reversephase chromatography to give the desired product (29 mg, 39% yield) as alight yellow solid. MS (ESI) m/z: 724.3 [M+H]⁺.

Example 238:3-(5-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-188)

Step 1. Synthesis of3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl4-methylbenzenesulfonate

To a solution3-(5-(3-hydroxyprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(75 mg, 0.26 mmol) and TEA (52 mg, 0.52 mmol) in DCM (5 mL) was added4-methylbenzenesulfonyl chloride (59 mg, 0.31 mmol) at room temperature,then it was stirred at room temperature for 2 h. The mixture wasconcentrated and purified by reverse phase chromatography to give thedesired product (58 mg, 47% yield) as a light yellow solid. MS (ESI)m/z: 453.1 [M+H]⁺.

Step 2. Synthesis of3-(5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-188)

A mixture of3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl4-methylbenzenesulfonate(40 mg, 0.08 mmol),(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(37 mg, 0.08 mmol), K₂CO₃ (2.2 mg, 0.16 mmol) and NaI (1.5 mg, 0.01mmol) in CH₃CN (3 mL) were stirred at 80° C. for 5 h. LCMS showed thereaction was completed. The mixture was concentrated and purified byreverse phase chromatography to give the desired product (21 mg, 36%yield) as a light yellow solid. MS (ESI) m/z: 724.3 [M+H]⁺.

Example 239:3-(6-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-189)

Step 1. Synthesis of(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)glycine

To a mixture of To the mixture of3-(6-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (130 mg, 501.43umol) and oxaldehydic acid (55.69 mg, 752.14 umol) in MeOH (5 mL) andTHF (1 mL) was added Pd/C (10%, 10 mg) at room temperature, theresulting mixture was stirred at 45° C. under H₂ for 16 h and monitoredby LCMS. The reaction mixture was filtrated and concentrated to givecrude product which was slurried (EtOAc/MeOH=5/1, 5 mL), filtrated togive desired product (150 mg, 94% yield) as a brown solid. MS (ESI) m/z:318.3 [M+H]⁺.

Step 2. Synthesis of3-(6-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-189)

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(4.4 mg, 9.92 umol) and(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)glycine (3.15 mg, 9.92umol) in DMSO (2 mL) were added HATU (4.52 mg, 11.90 umol) and DIEA(2.56 mg, 19.84 umol) at RT. The reaction mixture was stirred at roomtemperature for 16 h, then it was quenched with H₂O (10 mL) andextracted with DCM (10 mL*3). The combined organic layers were washedwith aqueous NaCl (10 mL*2), dried over Na₂SO₄, concentrated andpurified by Prep-TLC (DCM/MeOH=10/1) to give desired product (6 mg, 81%yield) as a yellow solid. MS (ESI) m/z: 743.8 [M+H]⁺.

Example 240:3-(5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-190)

Step 1. Synthesis of(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)glycine

To a solution of 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione(130 mg, 501.43 umol) and oxaldehydic acid (55.69 mg, 752.14 umol) inMeOH (5 mL) and THF (1 mL) was added Pd/C (6.09 mg, 50.14 umol.) at rtthe resulting mixture was stirred at 45+ C. under H₂ for 16 h andmonitored by LCMS. The reaction mixture was fitrated and concentrated togive crude product which was slurried (EtOAc/MeOH=5/1, 5 mL), fitratedto desired product (130 mg, 81.712% yield) as a brown solid. MS (ESI)m/z: 318.3 [M+H]⁺.

Step 2. Synthesis of3-(5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-190)

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(4.4 mg, 9.92 umol) and(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)glycine (3.15 mg, 9.92umol) in DMSO (2 mL) was added HATU (4.52 mg, 11.90 umol) and DIEA (2.56mg, 19.84 umol) at RT. The reaction mixture was stirred at roomtemperature for16 h, then it was quenched with H₂O (10 mL) and extractedwith DCM (10 mL*3). The combined organic layers were washed with aqueousNaCl (10 mL*2), dried over Na₂SO₄, concentrated and purified by Prep-TLC(DCM/MeOH=10/1) to give desired product (5.8 mg, 79% yield) as a yellowsolid. MS (ESI) m/z: 743.9 [M+H]⁺.

Example 241:3-(5-((2-(4-(6-(6((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-191)

Step 1. Synthesis of(R)-3-(6-(4-(2,2-dimethoxyethyl)piperazin-1-yl)pyridin-2-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine

To a suspension of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(200 mg, 450.94 umol) in CH₃CN (5 mL) were added2-bromo-1,1-dimethoxy-ethane (114.32 mg, 676.41 umol) and K₂CO₃ (124.46mg, 901.88 umol) at room temperature under the N₂, the resulting mixturewas warmed to 75° C. and stirred for 16 h. Then it was cooled to roomtemperature and concentrated, the residue was purified by silica gelchromatography (DCM/MeOH=20/1-10/1) to give desired product (200 mg, 83%yield) as a yellow solid. MS (ESI) m/z: 532.7 [M+H]⁺.

Step 2. Synthesis of(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetaldehyde

To a solution of(R)-3-(6-(4-(2,2-dimethoxyethyl)piperazin-1-yl)pyridin-2-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine(250 mg, 470.26 umol) dioxane (6 mL) was added cone. HCl (3 mL) at RT,the reaction mixture was warmed to 50° C. and stirred for 16 h. Then itwas concentrated to give crude product (220 mg, 96% yield) as a yellowsolid which was used directly in the next step without furtherpurification. MS (ESI) m/z: 504.5 [M+H]⁺.

Step 3. Synthesis of3-(5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-191)

To a solution of(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetaldehyde(48 mg, 98.86 umol) and3-(6-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (38.44 mg, 148.28umol) in MeOH (1 mL), DCE (2 mL) and AcOH (1 mL) was added NaBH₃CN(12.46 mg, 197.71 umol) at RT. The reaction mixture was stirred at roomtemperature for 16 h, then it was purified by prep-HPLC to give 10 mgcrude product which was further purified by prep-TLC(DCM/MeOH=10/1) todesired product (1.4 mg, 2% yield) as a yellow solid. MS (ESI) m/z:729.7 [M+H]⁺.

Example 242: Synthesis of2-(2,6-Dioxopiperidin-3-yl)-5-((2-((1-(6-(6-(((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)ethyl)amino)isoindoline-1,3-dione(TR-192)

Step 1. Synthesis of tert-butyl(R)-(1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)carbamate

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine(50 mg, 132.6 umol) in DMSO (3 mL) were added KF (23 mg, 397.8 umol) andtert-butyl azetidin-3-ylcarbamate (68.2 mg, 397.8 umol). The resultingmixture was stirred at 130° C. for 1 hr. After the Imide was totallyconsumed, the reaction was poured into water (20 mL) and extracted withethyl acetate (3×10 mL). The combined organic layers were washed withsaturated brine (20 mL), dried over anhydrous sodium sulfate, filteredand evaporated under reduced pressure. The resulting residue waspurified by reverse -phase chromatography to afford the desired producttert-butyl(R)-(1(6-(6(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)carbamate(21 mg, 30% yield) as a light yellow solid. MS (ESI) m/z: 530.3 [M+H]⁺.

Step 2. Synthesis of(R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-amine

To a solution of tert-butyl(R)-(1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)carbamate(100 mg, 188.9 umol) in DCM (2 mL) was added TFA (2 mL). The resultingmixture was stirred at 25° C. for 5 hr. After the starting material wastotally consumed, the reaction was evaporated under reduced pressure.The resulting residue was purified by reverse-phase chromatography toyield the desired product(R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-amine(73 mg, 91% yield) as a light yellow solid. MS (ESI) m/z: 430.2 [M+H]⁺.

Step 3. Synthesis of tert-butyl(R)-(2-((1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)ethyl)carbamate

To a solution of(R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-amin(100 mg, 232.9 umol) in DMAC (2 mL) were added Na₂CO₃ (74 mg, 698.8umol), NaI (34.7 mg, 232.9 umol) and tert-butyl (2-bromoethyl)carbamate(155 mg, 698.8 umol). The resulting mixture was stirred at 60° C. for 15hr. After the starting material was totally consumed, the reaction wasevaporated under reduced pressure. The resulting residue was purified byreverse -phase chromatography to yield the desired product tert-butyl(R)-(2-((1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)ethyl)carbamate(39 mg, 30% yield) as a light yellow solid. MS (ESI) m/z: 573.3 [M+H]⁺.

Step 4. Synthesis of(R)-N1-(1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)ethane-1,2-diamine

To a solution oftert-butyl(R)-(2((1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)ethyl)carbamate(39 mg, 69,6 umol) in DCM (2 mL) was added TFA (2 mL). The resultingmixture was stirred at 25° C. for 5 hr. After the starting material wastotally consumed, the reaction was evaporated under reduced pressure.The resulting residue was purified by reverse-phase chromatography toyield the desired product(R)-N1-(1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)ethane-1,2-diamine(25 mg, 76% yield) as a light yellow solid. MS (ESI) m/z: 473.2 [M+H]⁺.

Step 5. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-((2-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)ethyl)amino)isoindoline-1,3-dione(TR-192)

To a solution of(R)-N1-(1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)ethane-1,2-diamine(20 mg, 42.3 umol) in DMSO (3 mL) were added KF (7.4 mg, 127.1 umol) and2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (35 mg,127.1umol). The resulting mixture was stirred at 130° C. for 1 hr. After thePrimary amine was totally consumed, the reaction was poured into water(20 mL) and extracted with ethyl acetate (3×10 mL). The combined organiclayers were washed with saturated brine (20 mL), dried over anhydroussodium sulfate, filtered and evaporated under reduced pressure. Theresulting residue was purified by reverse-phase chromatography to affordthe desired product2-(2,6-dioxopiperidin-3-yl)-5-((2-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)ethyl)amino)isoindoline-1,3-dione(9.2 mg, 30% yield) as a light yellow solid. MS (ESI) m/z: 729.3 [M+H]⁺.

Example 243: Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-((2-(1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)ethyl)amino)isoindoline-1,3-dione(TR-193)

TR-193 was synthesized following the standard procedure for preparingTR-175. MS (ESI) m/z: 714.3 [M+H]⁺.

Example 244:2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropyl)isoindoline-1,3-dione(TR-194)

Step 1. Synthesis of(E)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acrylic acid

A mixture of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(200 mg, 0.60 mmol), acrylic acid (65 mg, 0.90 mmol), Pd(PPH₃)₄ (69 mg,0.06 mmol) and TEA (182 mg, 1.8 mmol) in DMSO (15 mL) was stirred at 90°C. for 16 h. The reaction mixture was concentrated and the residue waspurified by reverse phase chromatography to give the desired product (82mg, 42% yield) as a pale brown solid. MS (ESI) m/z: 327.1 [M+H]⁺.

Step 2. Synthesis of3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propanoic acid

A mixture of(E)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acrylic acid(50 mg, 0.15 mmol) and Pd/C (10 mg) in methanol (5 mL) was stirred underH₂ (1 atm, balloon) at room temperature for 3 h. The reaction mixturewas purified by reverse phase chromatography to give the desired product(31 mg, 62% yield) as a light brown solid. MS (ESI) m/z: 329.1 [M+H]⁺.

Step 3. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxopropyl)isoindoline-1,3-dione(TR-194)

A mixture of3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propanoic acid(20 mg, 0.06 mmol),(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine (27 mg, 0.06 mmol), EDCI (17 mg, 0.09 mmol),NMM (30 mg, 0.30 mmol) and HOAT (12 mg, 0.09 mmol) in DMSO (1.5 mL) werestirred at room temperature for 16 h. LCMS showed the reaction wascompleted. The mixture was concentrated and purified by reverse phasechromatography to give the desired product (16 mg, 36% yield) as a lightyellow solid. MS (ESI) m/z: 756.3 [M+H]⁺.

Example 245:2-(2,6-Dioxopiperidin-3-yl)-5-((E)-3-(4-(6-(6((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxoprop-1-en-1-yl)isoindoline-1,3-dione(TR-195)

A mixture of(E)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acrylic acid(20 mg, 0.06 mmol),(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine (27 mg, 0.06 mmol), EDCI (17 mg, 0.09 mmol),NMM (30 mg, 0.30 mmol) and HOAT (12 mg, 0.09 mmol) DMSO (1.5 mL) werestirred at room temperature for 16 h. LCMS showed the reaction wascompleted. The mixture was concentrated and purified by reverse phasechromatography to give the desired product (21 mg, 46% yield) as a lightyellow solid. MS (ESI) m/z: 754.3 [M+H]⁺.

Example 246:3-(6-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin4-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-196)

To a solution of(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetaldehyde(5 mg, 10.30 umol) and3-(6-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3 mg, 11.57 umol)in DMF (1 mL) were added TMSCI (3.34 mg, 30.89 umol) and NaBH₄ (782.61mg, 20.59 umol) at 0° C. The reaction mixture was stirred at 0° C. foranother 1.5 h, then it was warmed to room temperature and stirred for 16h. The reaction mixture was purified by prep-HPLC to give 5 mg of crudeproduct which was further purified by prep-TLC (DMC/MeOH=10/1) to givedesired product (2.15 mg, 29% yield) as a white solid. MS (ESI) m/z:729.8 [M+H]⁺.

Example 247:2-(2,6-Dioxopiperidin-3-yl)-5-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)isoindoline-1,3-dione(TR-197)

Step 1. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-methylisoindoline-1,3-dione

The mixture of isobenzofuran-1,3-dione (15 g, 101.27 mmol),3-aminopiperidine-2,6-dione (19.46 g, 151.91 mmol) and NaOAc (101.27mmol) were stirred in AcOH (300 mL) at 100° C. for 16 h. LCMS showed thereaction was completed. The solvent was removed under vacuum to give thecrude product which was used for next step without further purification(25 g, 90% yield). MS (ESI) m/z: 273.4 [M+H]⁺.

Step 2. Synthesis of5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

The mixture of 2-(2,6-dioxopiperidin-3-yl)-5-methylisoindoline-1,3-dione(1 g, 3.67 mmol), NBS (719.1.0 mg, 4.04 mmol) and BPO (45.41 mg, 734.60umol) in CH₃CN (50 mL) were stirred at 90° C. for 4 h. The solvent wasremoved under vacuum to give the crude product which was purified bysilica gel chromatography (petroleum ether/EtOAc=5/1) to give thedesired product as an off-white solid (1 g, 58% yield). MS (ESI) m/z:353.3 [M+H]⁺.

Step 3. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)isoindoline-1,3-dione(TR-197)

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(0.020 g, 45.09 umol) in DCM (5 mL) was added5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (47.50mg, 135.28 umol), then the reaction was stirred for 16 h. LCMS showedthe reaction was completed. The mixture was purified by Prep-TLC(DCM/MEOH=100/2) to give the desired product as an off-white solid (1.9mg, 6% yield). MS (ESI) m/z: 714.7 [M+H]⁺.

Example 248:2-(2,6-Dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione(TR-198)

Step 1. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione

The mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione(2 g, 7.24 mmol), azetidin-3-ylmethanol (693.88 mg, 7.96 mmol) and TEA(2.20 g, 21.72 mmol) were stirred in DMF (10 mL) at 85° C. for 1 h. LCMSshowed the reaction was completed. The mixture was extracted with EtOAc,washed with brine, dried over Na₂SO₄, concentrated to give the crudeproduct which was purified by reverse phase chromatography to give thedesired product as a yellow solid (800 mg, 32% yield). MS (ESI) m/z:344.2 [M+H]⁺.

Step 2. Synthesis of(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl4-methylbenzenesulfonate

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione(0.034 g, 99.03 umol) and DMAP (24.20 mg, 198.06 umol) in pyridine (2mL) was added TsCl (13.97 mg, 198.06 umol), then the reaction wasstirred for 4 h. The mixture was purified by silica gel chromatography(petroleum ether/EtOAc=1/1) to give the product as a yellow solid whichwas further purified by reverse phase chromatography to give thepurified product as a yellow solid (25 mg, 51% yield). MS (ESI) m/z:498.4 [M+H]⁺.

Step 3. Synthesis of2-(2,6-Dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione(TR-198)

The mixture of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(0.015 g, 33.82 umol),(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl4-methylbenzenesulfonate (21.00 mg, 42.21 umol), K₂CO₃ (14.00 mg, 101.46umol) and NaI (10.14 mg, 67.64 umol) in CH₃CN (3 mL) were stirred at 82+C. for 16 h. LCMS showed the reaction was completed. The mixture waspurified by reverse phase chromatography to give the desired product asa yellow solid (12 mg, 46% yield). MS (ESI) m/z: 769.8 [M+H]⁺.

Example 249:2-(2,6-Dioxopiperidin-3-yl)-5-((3-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)propyl)amino)isoindoline-1,3-dione(TR-199)

Step 1. Synthesis of 2-(2-cyanoethoxy)ethyl 4-methylbenzenesulfonate

To a solution 3-(2-hydroxyethoxy)propanenitrile (100 mg, 868.58 umol) inDCM (5 mL) were added C4-methylbenzenesulfonyl chloride (250 mg, 1.31mmol) and DMAP (21.22 mg, 173.72 umol) DIPEA (336.77 mg, 2.61 mmol). Theresulting solution was stirred at 10° C. overnight. The resultingresidue was purified by reverse-phase chromatography to yield thedesired product as a white solid (178 mg, 76% yield). MS (ESI) m/z:270.8 [M+H]⁺.

Step 2. Synthesis of(R)-3-(2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)propanenitrile

A solution(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(108 mg, 243.51 umol) in ACN (5 mL) were added C2-(2-cyanoethoxy)ethyl4-methylbenzenesulfonate (178 mg, 660.93 umol) and NaI (11.9 mg, 79.39umol) K₂CO₃ (165 mg, 1.20 mmol). The resulting solution was stirred at80° C. overnight. The resulting residue was purified by reverse-phasechromatography to yield the desired product as a white solid (100 mg,76% yield). MS (ESI) m/z: 541.5 [M+H]⁺.

Step 3. Synthesis of(R)-3-(2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)propan-1-amine

A solution(R)-3-(2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)propanenitrile(100 mg, 184.97 umol) in MeOH (5 mL) were added NaBH₄ (130 mg, 184.97umol) CoCl₂, (50 mg, 184.97 umol). The resulting solution was stirred at0° C. overnight. The resulting residue was quenched by ammonia,concentrated, diluted with 10 ml 1% HCl and extracted with DCM/MeOH=10/1(10 mL). The organic phase was concentrated and the residue was purifiedby reverse-phase chromatography to yield the desired product as a whitesolid (20 mg, 20% yield). MS (ESI) m/z: 545.6 [M+H]⁺.

Step 4. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-((3-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)propyl)amino)isoindoline-1,3-dione(TR-199)

A solution(R)-3-(2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)propan-1-amine(20 mg, 36.72 umol) in DMSO (1 mL) were added KF (2.13 mg, 36.72 umol)and 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (10 mg,36.20 umol). The resulting solution was stirred at 105° C. for 8 h. Theresulting residue was purified by reverse-phase chromatography to yieldthe desired product as a white solid (5 mg, 17% yield). MS (ESI) m/z:801.8 [M+H]⁺.

Example 250:3-(5-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-200)

TR 200 was synthesized following the standard procedure for preparingTR-201. MS (ESI) m/z: 730.7 [M+H]⁺.

Example 251:3-(6-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-201)

Step 1. Synthesis of(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol

A mixture of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(500 mg, 1.12 mmol), 2-bromoethan-1-ol (211.6 mg, 1.69 mmol), K₂CO₃ (463mg, 3.36 mmol) and NaI (169.3 mg, 1.12 mmol) in DMF (20 mL) were stirredat 100° C. for 16 h. The mixture was filtered and purified by reversephase chromatography to give the desired product (159 mg, 29% yield). MS(ESI) m/z: 488.3 [M+H]⁺.

Step 2. Synthesis of(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl-methylbenzenesulfonate

To a solution(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol(159 mg, 0.327 mmol) and TEA (99 mg, (0.98 mmol) in DCM (15 mL) wasadded 4-methylbenzenesulfonyl chloride (93 mg, 0.49 mmol) at roomtemperature, then it was stirred at room temperature for 4 h. Themixture was concentrated and purified by reverse phase chromatography togive the desired product (121 mg, 58% yield) as white solid. MS (ESI)m/z: 642.1 [M+H]⁺.

Step 3. Synthesis of3-(6-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

A mixture of(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl4-methylbenzenesulfonate (100 mg, 0.15 mmol),3-(6-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60.8 mg, 0.23mmol), K₂CO₃ (61.6 mg, 0.45 mmol) and NaI (22.4 mg, 0.15 mmol) in CH₃CN(3 mL) were stirred at 80° C. for 5 h. LCMS showed the reaction wascompleted. The mixture was concentrated and purified by reverse phasechromatography to give the desired product (32.8 mg, 30% yield) as awhite solid. MS (ESI) m/z: 730.7 [M+H]⁺.

Example 252:5-((2-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(1-methyl-2,6-dioxopipenidin-3-yl)isoindoline-1,3-dione(TR-123 neg)

Step 1. Synthesis of tert-butyl(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycinate

To a solution of5-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (100mg, 0.34 mmol) in DMSO (3 mL) were added KF (39 mg, 0.68 mmol) andtert-butyl glycinate (89 mg, 0.68 mmol). The resulting mixture wasstirred at 130° C. for 5 h. The reaction was cooled to room temperaturebefore H₂O (50 mL) was added. The mixture was extracted with EtOAc (10mL×3). The combined organic layers were concentrated and the resultingresidue was purified by reverse phase chromatography to give the desiredproduct (82 mg, 61% yield) as pale brown solid. MS (ESI) m/z 402.2[M+H]⁺.

Step 2. Synthesis of(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin -5-yl)glycine

A mixture of tert-butyl(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycinate(80 mg, 0.20 mmol) in HCOOH (88%, 5 mL) was stirred at room temperaturefor 16 h. The mixture was concentrated and the resulting residue waspurified by reverse phase chromatography to give the desired product (54mg, 78% yield) as pale brown solid. MS (ESI) m/z 346.1 [M+H]⁺.

Step 3. Synthesis of5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

TR-123 neg was synthesized following the standard procedure forpreparing TR-053 (18 mg, yield 51%). MS (ESI) m/z: 771.3 [M+H]⁺.

Example 253:3-(6-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3yl)pyridin-2-yl)piperazin-1-yl)-3-oxoprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-202)

Step 1. Synthesis of3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)propiolic acid

A mixture of3-(6-(3-hydroxyprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.34 mmol), TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy freeradical) (5.2 mg, 0.034 mmol), acetonitrile (3 mL) and sodium phosphatebuffer (1.3 mL, 0.67 M, pH=6.7) was stirred at 35° C. A solution ofsodium chlorite was prepared by dissolving 80% NaClO₂ (9.14 g, 80.0mmol) in water (40 mL) and a solution of dilute NaOCl was prepared bydiluting household bleach (5.25% NaOCl, 1.06 mL, ca. 2.0 mol %) withwater (19 mL). Then NaClO₂ solution (0.4 mL) was added followed by thedilute solution of NaOCl solution (0.2 mL). The resulting mixture wasstirred at 35° C. until the reaction was completed. The reaction mixturewas purified by reverse-phase chromatography to give the desired product(72 mg, 69% yield) as a light yellow solid. MS (ESI) m/z: 313.1 [M+H]⁺.

Step 2. Synthesis of3-(6-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxoprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)propiolic acid (10mg, 32.1 umol) in DMSO (1.5 mL) were added HOAt (6.5 mg, 48.1 umol),EDCI (9.2 mg, 48.1 umol), NMM (32.4 mg, 321.0 umol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(14.2 mg, 32.1 umol) sequentially. After the resulting solution wasstirred at 25° C. for 16 h, the reaction was poured into water (50 mL)and extracted with ethyl acetate (3×20 mL). The combined organic layerswere washed with saturated brine (50 mL). dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by reverse-phasechromatography to give the desiredproduct3-(6-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxoprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(11.3 mg, 48% yield) as a light yellow solid. MS (ESI) m/z: 738.3[M+H]⁺.

Example 254:3-(5-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxoprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-203)

Step 1. Synthesis of3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)propiolic acid

A mixture of3-(5-(3-hydroxyprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.34 mmol), TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy freeradical) (5.2 mg, 0.034 mmol), acetonitrile (3 mL) and sodium phosphatebuffer (1.3 mL, 0.67 M, pH=6.7) was stirred at 35° C. A solution ofsodium chlorite is prepared by dissolving 80% NaClO ₂ (9.14 g. 80.0mmol) in water (40 mL) and a solution of dilute NaOCl is prepared bydiluting household bleach (5.25% NaOCl, 1.06 mL, ca. 2.0 mol %) withwater (19 mL). Then NaClO₂ solution (0.4 mL) was added followed by thedilute NaOCl solution (0.2 mL). The resulting mixture was stirred at 35°C. until the reaction was completed. The reaction mixture was purifiedby reverse-phase chromatography to give the desired product (65 mg, 63%yield) as a light yellow solid. MS (ESI) m/z: 313.1 [M+H]⁺.

Step 2. Synthesis of3-(5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxoprop-1-yn-1-yl)-1-oxoisoindolin2-yl)piperidine-2,6-dione

TR-203 was synthesized following the standard procedure for preparingTR-202 (9.8 mg, 42% yield) as a light yellow solid. MS (ESI) m/z: 738.3[M+H]⁺.

Example 255:2-(2,6-Dioxopiperidin-3-yl)-5-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)isoindoline-1,3-dione(TR-204)

Step 1. Synthesis of dimethyl 4-bromophthalate

To a solution of 5-bromoisobenzofuran-1,3-dione (4.6 g, 20.26 mmol) inMeOH (50 mL) was added H₂ SO₄ (992.90 mg, 10.13 mmol) at roomtemperature. After the reaction mixture was stirred at 80° C. for 16 h,the crude product was dissolved in DCM (50 mL), washed with aq. NaHCO₃(100 mL) and brine (100 mL). The organic phase was dried over Na₂SO₄,filtered, and concentrated. The resulting residue was purified by silicagel chromatography (petroleum ether/EtOAc=10:1) to give dimethyl4-bromophthalate (5.0 g, 90% yield) as colorless oil. MS (ESI) m/z:375.0 [M+H]⁺.

Step 2. Synthesis of dimethyl 4-(2-(benzyloxy)ethyl)phthalate

To a solution of 2-benzyloxyethyl(trifluoro)boronpotassium hydride (800mg, 3,30 mmol) and dimethyl 4-bromophthalate (1.08 g, 3.97 mmol) intoluene (20 mL) and H₂O (10 mL) were addedbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(233.97 mg, 330.46 nmol) and Cs₂CO₃ (2.15 g, 6.61 mmol) at roomtemperature under N₂. After the reaction mixture was stirred at 100° C.for 16 h, the solvent was removed under reduced pressure. The resultingcrude product was purified by silica gel chromatography (petroleumether/EtOAc=10:1) to give dimethyl 4-(2-(benzyloxy)ethyl)phthalate (960mg, 88% yield) as colorless oil. MS (ESI) m/z: 329.6 [M+H]⁺.

Step 3. Synthesis of 4-(2-(benzyloxy)ethyl)phthalic acid

To a solution of dimethyl 4-(2-(benzyloxy)ethyl)phthalate (1.0 g, 3.05mmol) in MeOH (10 mL), THF (10 mL) and H₂O (10 mL) was added NaOH(730.91 mg, 18.27 mmol) at room temperature. After the reaction mixturewas stirred at 80° C. for 3 h, organic solvents were removed underreduced pressure. The resulting aqueous mixture was acidified with cone.HCl to pH=2, before being extracted with DCM (3×20 mL). The organiclayers were combined, dried over Na₂SO₄, filtered and concentrated togive crude 4-(2-benzyloethyl)phthalic acid (900 mg, 98% yield) as ayellow solid. This product was used in the next step directly withoutfurther purification. MS (ESI) m/z: 301.3 [M+H]⁺.

Step 4. Synthesis of5-(2-(benzyloxy)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

A solution of 4-(2-benozyloxyethyl)phthalic acid (800 mg, 2.66 mmol) and3-aminopiperidine-2,6-dione (341.3 mg, 2.66 mmol) in pyridine (40 mL)was stirred at 120° C. for 16 h. Then the reaction mixture wasconcentrated and purified. by silica gel chromatography (DCM/MeOH=20:1)to give5-(2-(benzyloxy)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(0.98 g, 94% yield) as a yellow solid. MS (ESI) m/z: 393.3 [M+H]⁺.

Step 5. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(2-hydroxyethyl)isoindoline-1,3-dione

To a solution of5-(2-(benzyloxy)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(700 mg, 1.78 mmol) in THF (25 mL) were added Pd(OH)₂ (50 mg) and Pd/C(50 mg) at room temperature. Then the reaction mixture was stirred at50° C. for 16 h under hydrogen atmosphere pressure. After cooled down toroom temperature, the mixture was filtered and concentrated to givecrude2-(2,6-dioxopiperidin-3-yl)-5-(2-hydroxyethyl)isoindoline-1,3-dione (500mg, 93% yield) as a white solid. This product was used in the next stepdirectly without further purification. MS (ESI) m/z: 303.2 [M+H]⁺.

Step 6. Synthesis of2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ethyl4-methylbenzenesulfonate

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-(2-hydroxyethyl)isoindoline-1,3-dione (25mg, 82.70 umol) in TEA (5 mL) was added 4-methylbenzenesulfonyl chloride(15.77 mg, 82.70 umol) at 0° C. After the reaction mixture was stirredat room temperature for 2 h, the mixture was concentrated and purifiedby prep-TLC (DCM/MeOH=20:1) to give crude2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ethyl4-methylbenzenesulfonate (20 mg, 53% yield). This product was used inthe next step directly without further purification MS (ESI) m/z: 457.3[M+H]⁺.

Step 7. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)isoindoline-3-dione

To a solution(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(14.57 mg, 32.86 umol) and2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ethyl4-methylbenzenesulfonate (15 mg, 32.86 umol) in CH₃CN (4 mL) were addedNaI (9.85 mg, 65.72 umol) and K₂ CO₃ (18.14 mg, 131.44 umol) at roomtemperature under N₂. After the reaction mixture was stirred at 80° C.for 16 h, the solvent was removed and the resulting residue was purifiedby prep-TLC (DCM/MeOH=10:1) to give2-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)isoindoline-1,3-dione(14 mg, 59% yield) as a light yellow solid. MS (ESI) m/z: 729.6 [M+H]⁺.

Example 256:3-(5-(3-((4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-205)

Step 1. Synthesis oftert-butyl3-((benzyloxy)methyl)azetidine-1-carboxylate

To a solution of tert-butyl3-(hydroxymethyl)azetidine-1-carboxylate (2g, 10.0 mmol) and NaH (720 mg, 30.0mmol) in THF (50 mL) was added BnBr(2.74 g, 15.0 mmol) in portions at 0° C. under N₂. The resulting mixturewas stirred at room temperature for 5 h, beofre the reaction wasquenched with H₂O (100 mL) at 0° C. and extracted with DCM (100 mL×2).The organic layers were combined and dried over Na₂SO₄, filtered, andconcentrated. The resulting residue was purified by silica gel flashchromatography (petroleum/ethyl acetate=2:1) to give tert-butyl3-((benzyloxy)methyl)azetidine-1-carboxylate (1.5 g, 51% yield) as alight yellow oil. MS (ESI) m/z: 278.3 [M+H]⁺.

Step 2. Synthesis of 3-((benzyloxy)methyl)azetidine

To a solution of tert-butyl3-((benzyloxy)methyl)azetidine-1-carboxylate(1.5 g, 5.4 mmol) in DCM (15 mL) was added TFA (3 mL) at 0° C. After thereaction mixture was stirred at room temperature for 1 h, the solventwas removed under vacuum. The resulting residue was washed with diethylether to give 3-((benzyloxy)methyl)azetidine (1.0 g, 76% yield) as ayellow oil. MS (ESI) m/z: 178.2 [M+H]⁺.

Step 3. Synthesis of5-(3-((benzyloxy)methyl)azetidin-1-yl)isobenzofuran-1(3H)-one

To a solution of 3-((benzyloxy)methyl)azetidine (1.0 g, 5.6 mmol) and5-bromoisobenzofuran-1(3H)-one (1.19 g, 5.6 mmol) in DMSO (15 mL) wereadded Cs₂CO₃ (5.4 g, 16.8 mmol) and Ruphos-Pd-G3 (470 mg, 0.54 mmol) atroom temperature under N₂. After the reaction mixture was stirred at 80°C. for 12 h, the resulting black mixture was diluted with ethyl acetate(20 mL), washed with saturated aqueous brine (2×20 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated. The resulting residue was purified by silica gel flashchromatography (petroleum/ethyl acetate=1:1) to give5-(3-((benzyloxy)methyl)azetidin-1-yl)isobenzofuran-1(3H)-one (470 mg,27% yield) as a brown solid. MS (ESI) m/z: 310.1 [M+H]⁺.

Step 4. Synthesis of4-(3-((benzyloxy)methyl)azetidin-1-yl)-2-(hydroxymethyl)benzoic acid

To a solution of 5-(3-((benzyloxy)methyl)azetidin-1-yl)isobenzofuran-1(470 mg, 1.5 mmol) in MeOH (15 mL) was added NaOH (181 mg, 4.5 mmol) atroom temperature. Then the mixture was stirred at 60° C. for 2 h. Aftercooled down to room temperature, the solution was acidified to pH=2-3with 1 N HCl and filtered. The filter cake was washed withEtOAc/petroleum ether (50 mL, 1:10) to give4-(3-((benzyloxy)methyl)azetidin-1-yl)-2-(hydroxymethyl)benzoic acid(350 mg, 74% yield) as a yellow solid. MS (ESI) m/z: 328.2 [M+H]⁺.

Step 5. Synthesis of methyl4-(3-((benzyloxy)methyl)azetidin-1-yl)-2-(hydroxymethyl)benzoate

To a solution of4-(3-((benzyloxy)methyl)azetidin-1-yl)-2-(hydroxymethyl)benzoic acid(350 mg, 1.06 mmol) in EtOAc/MeOH (15 mL) was added TMSCHN₂ (1 mL) at 0°C. After the completion of addition, the reaction mixture was stirred atroom temperature for 1 h, then concentrated to give crude methyl4-(3-((benzyloxy)methyl)azetidin-1-yl)-2-(hydroxymethyl)benzoate (220mg, 62% yield) as a yellow solid. This product was used in the next stepdirectly without further purification. MS (ESI) m/z: 342.2 [M+H]⁺.

Step 6. Synthesis of methyl4-(3-((benzyloxy)methyl)azetidin-1-yl)-2-(((methylsulfonyl)oxy)methyl)benzoate

To a solution of methyl4-(3-((benzyloxy)methyl)azetidin-1-yl)-2-(hydroxymethyl)benzoate (220mg, 0.64 mmol) in DCM (10 mL) were added MsCl (0.5 mL) and DIEA (248mg,1.92 mmol) at 0° C. Then the reaction was stirred at room temperaturefor 1 h, quenched the reaction with water (30 mL). The resultingsolution was extracted with DCM (20 mL×2) and the organic layer wasconcentrated to give methyl4-(3-((benzyloxy)methyl)azetidin-1-yl)-2-(((methylsulfonyl)oxy)methyl)benzoate(150 mg, 55% yield) as a yellow solid. This product was used in the nextstep directly without further purification. MS (ESI) m/z: 342.2 [M+H]⁺.

Step 7. Synthesis of3-(5-(3-((benzyloxy)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of methyl4-(3-((benzyloxy)methyl)azetidin-1-yl)-2-(((methylsulfonyl)oxy)methyl)benzoate(150 mg, 0.35 mmol) in acetonitrile (5 ml) were added3-aminopiperidine-2,6-dione (44 mg, 0.35 mmol) and potassium carbonate(1.50 mg, 1.05)nmol) at room temperature. The mixture was stirred atroom temperature for 2 h. The solvent was removed under vacuum and theresidue was purified by silica gel flash chromatography (MeOH/DCM=1:10)to give3-(5-(3-((benzyloxy)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(40 mg, 26% yield) as a white solid. MS (ESI) m/z: 420.8 [M+H]⁺.

Step 8. Synthesis of3-(5-(3-(hydroxymethyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of3-(5-(3-((benzyloxy)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(40 mg, 0.09 mmol) in DCM (5 mL) was added MsOH (1 mL) at 0° C. Thereaction was stirred at room temperature for 2 h, then the solvent wasremoved under vacuum. The residue was purified by silica gel flashchromatography (MeOH/H₂O=1:1) to give3-(5-(3-(hydroxymethyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(26 mg, 83% yield) as a yellow solid. MS (ESI) m/z: 330.1 [M+H]⁺.

Step 9. Synthesis of(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-3-yl)methyl4-methylbenzenesulfonate

To a solution of3-(5-(3-(hydroxymethyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(26mg, 0.08 mmol) in dichloromethane (2 mL) were added TsCl (30 mg, 0.16mmol) and DMAP (20 mg, 0.08 mmol) at room temperature. The mixture wasstirred at room temperature for 3 h. The reaction was concentrated andpurified by silica gel flash chromatography (MeOH/DCM=1:10) to give(1(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-3-yl)methyl4-methylbenzenesulfonate (13 mg, 34% yield) as a yellow solid. MS (ESI)m/z: 484.2 [M+H]⁺.

Step 10. Synthesis of3-(5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-3-yl)methyl4-methylbenzenesulfonate(13 mg, 0.03 mmol) and(S)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(12 mg, 0.03 mmol) acetonitrile (1 mL) were added potassium carbonate(11 mg, 0.09 mmol) and sodium iodide (4 mg, 0.03 mmol) at roomtemperature. The reaction mixture was stirred at 80° C. for 2 h, thenconcentrated and purified by silica gel flash chromatography(MeOH/DCM=1:10) to give3-(5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(3.5 mg, 18% yield) as a withe solid. MS (ESI) m/z: 755.4 [M+H]⁺.

Example 257:3-(5-((1-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-206)

Step 1. Synthesis oftert-butyl3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)azetidine-1-carboxylate

To a solution of 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200 mg, 0.77 mmol) and AcOH (2 mL) in DCM (6 mL) was added 1M boranetetrahydrofuran complex solution (1.54 mL, 1.54 mmol) at 0° C., then itwas stirred at 0° C., for 2 h. The mixture was concentrated and purifiedby reverse-phase chromatography to give the desired product (61 mg, 19%yield) as a light yellow solid. MS (ESI) m/z: 415.2 [M+H]⁺.

Step 2. Synthesis of3-(5-(azetidin-3-ylamino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of tert-butyl3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)azetidine-1-carboxylate(30 mg, 0.072 mmol) in DCM (5 mL) was added TFA (4 mL) at roomtemperature, then it was stirred at room temperature for 2 h. Themixture was concentrated and purified by reverse-phase chromatography togive the desired product (18 mg, 79% yield) as a light yellow solid. MS(ESI) m/z: 315.1 [M+H]⁺.

Step 3. Synthesis of3-(5-((1-(6-(6((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solutionof3-(5-(azetidin-3-ylamino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (18mg, 0.057 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine(21 mg, 0.057 mmol) in DMSO (5 mL) was added KF (3.3 mg, 0.057 mmoL) atroom temperature, then it was stirred at 130° C. for 16 h. The reactionwas cooled to room temperature before H₂O (50 mL) was added. The mixturewas extracted with EtOAc (10 mL×3). The combined organic layers wereconcentrated and purified by reverse-phase chromatography to give thedesired product3-(5-((1-(6-((6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(5.5 mg, 1.4% yield) as a light yellow solid. MS (ESI) m/z: 672.3[M+H]⁺.

Example 258:3-(5-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-207)

TR-207 was synthesized following the standard procedure for preparing;TR-206 (4.8 mg, 15% yield) as a light yellow solid. MS (ESI) m/z: 686.3[M+H]⁺.

Example 259:3-(5-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-208)

Step 1. Synthesis of tert-butyl4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethynyl)piperidine-1-carboxylate

A mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100mg, 0.31 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (71 mg,0.34 mmol), Pd(dppf)Cl₂ (22 mg, 0.03 mmol), CuI (57 mg, 0.03 mmol) andDIPEA(79 mg, 0.62 mmol) in DMSO (10 mL) was stirred at 80° C. for 16 h.The reaction mixture was concentrated and the residue was purified byreverse-phase chromatography to give the desired product (55 mg, 39%yield) as a pale brown solid. MS (ESI) m/z: 452.2 [M+H]⁺.

Step 2. Synthesis of3-(1-oxo-5-(piperidin-4-ylethynyl)isoindolin-2-yl)piperidine-2,6-dione

To a solutionof tert-butyl4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethynyl)piperidine-1-carboxylate(55 mg, 0.12 mmol) in DCM (5 mL) was added TFA (4 mL) at roomtemperature. After it was stirred at room temperature for 2 h, themixture was concentrated and purified by reverse-phase chromatography togive the desired product (36 mg, 85% yield) as a light yellow solid. MS(ESI) m/z: 352.2 [M+H]⁺.

Step 3. Synthesis of3-(5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)ethynyl-1-oxoisoinindolin-2-yl)piperidine-2,6-dione

TR-208 was synthesized following the standard procedure for preparingTR-206 (6.2 mg, 15% yield) as a light yellow solid. MS (ESI) m/z: 709.3[M+H]⁺.

Example 260:N-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidine-3-carboxamide(TR-209)

Step . Synthesis of(R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidine-3-carboxylic acid

To a solutionof azetidine-3-carboxylic, acid (16 mg, 0 16 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine(50 mg, 0.13 mmol) in DMSO (8 mL) was added KF (7.5 mg, 0.13 mmol) atroom temperature. After it was stirred at 130° C. for 16 h, the reactionwas cooled to room temperature before H₂O (50 mL) was added. The mixturewas extracted with EtOAc (3×10 mL). The combined organic layers wereconcentrated and purified by reverse-phase chromatography to give thedesired product (22 mg, 37% yield) as a light yellow solid. MS (ESI)m/z: 459.2 [M+H]⁺.

Step 2. Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidine-3-carboxamide

TR-209 was synthesized following the standard procedure for preparingTR-202 (9.8 mg, 21% yield) as a light yellow solid. MS (ESI) m/z: 714.3[M+H]⁺.

Example 261:3-(5-(((1-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-210)

Step 1. Synthesis of tert-butyl 3-(((2-(2,6-dioxopiperidin-31)-1-oxoisoindolin-5-yl)amino)methyl)azetidine-1-carboxylate

To a solution of 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.38 mmol) and AcOH (2 mL) in DCM (6 mL) was added 1M boranetetrahydrofuran complex solution (0.76 mL, 0.76 mmol) at 0° C. After itwas stirred at 0° C. for 2 h, the mixture was concentrated and purifiedby reverse-phase chromatography to give the desired product (42 mg, 26%yield) as a light yellow solid. MS (ESI) m/z: 429.2 [M+H]⁺.

Step 2. Synthesis of3-(5-((azetidin-3-ylmethyl)amino)-1-oxoisoindolin-2-ylpiperidine-2,6-dione

To a solutionof tert-butyl3-(((2-(2,6-dioxopiperidin-3-yl)-oxoisoindolin-5-yl)amino)methyl)azetidine-1-carboxylate(42 mg, 0.10 mmol) in DCM. (5 mL) was added TFA (4 mL) at roomtemperature. After it was stirred at room temperature for 2 h, themixture was concentrated and purified by reverse-phase chromatography togive the desired product (25 mg, 78% yield) as a light yellow solid. MS(ESI) m/z: 329.2 [M+H]⁺.

Step 3. Synthesis of3-(5-(((1-(6(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

TR-210 was synthesized following the standard procedure for preparingTR-208 (6.7 mg, 15% yield) as a light yellow solid. MS (ESI) m/z: 686.3[M+H]⁺.

Example 262:2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carbnoyl)azetidin-1-yl)isoindoline-1,3-dione(TR-211)

Step 1. Synthesis of1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carboxylicacid

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (276 mg, 1.0mmol) and azetidine-3-carboxlicacid (171 mg, 1.5 mmol) in DMSO (3 mL)was added KF (232 mg,4.0 mmol). The resulting solution was stirred at120° C. for 5 h, before the reaction was quenched with water (10 mL),and extracted with ethyl acetate (2×20 mL). The organic layers werecombined, dried over Na₂SO₄, and concentrated. The resulting residue waspurified by reverse-phase chromatography to give1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carboxylicacid (175 mg, 49% yield) as a yellow solid. MS (ESI) m/z: 358.1 [M+H]⁺.

Step 2. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)isoinidoline-1,3-dione

To a solution of1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carboxylicacid (175 mg, 0.49 mmol) and6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]-3-(6-piperazin-1-yl-2-pyridyl)imidazo[1,2-b]pyridazine(217 mg, 0.49 mmol) in N,N-dimethylformamide (10 mL) were added HAUT(371 mg, 0.98 mmol) and DIEA (189 mg,1.46 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 2 h, before it wasquenched with water (30 mL). The resulting mixture was extracted withethyl acetate (3×20 mL). And the combined organic layers were dried oversodium sulfate, filtered, and concentrated. The resulign residue waspurified by silica gel chromatography (DCM/MeOH=10:1) to give2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)isoindoline-1,3-dione(128 mg, 33% yield) as a yellow solid. MS (ESI) m.z: 783.8 [M+H]⁺.

Example 263:3-(5-((1-(6-(6-((R)-2-(3-fluorophenl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-212)

Step 1. Synthesis of tert-butyl4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)piperidine-1-carboxylate

To a solution of 3-(5-amino-1-oxoisoindolin-2-yl) piperidine-2,6-dione(130 mg, 0.5 mmol) in dichloromethane (10 mL) and AcOH (2.0 mL) wereadded tert-butyl4-oxopiperidine-1-carboxylate (119 mg, 1.0 mmol) andBH₃/THF (0.5 ml) at room temperature. The mixture was stirred at roomtemperature for 16 h, then quenched with H₂O (20 mL) and extracted withdichloromethane (3×20 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated to afford crude tert-butyl4-((2(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)piperidine-1-carbaxylate(160 mg, 72% yield) as a green solid. This product was used in the nextstep directly without further purification. MS (ESI) m/z: 443.2 [M+H]⁺.

Step 2. Synthesis of3-(1-oxo-5-(piperidin-4-ylamino)isoindolin-2-yl)piperidine-2,6-dione

To a solution oftert-butyl4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)piperidine-1-carboxylate(160 mg, 0.36 mmol) in DCM (5 mL) was added TFA (1 mL) at 0° C. Thereaction mixture was stirred at room temperature for 16 h, before thesolvent was removed under vacuum. The resulting residue was washed withdiethyl ether to give3-(1-oxo-5-(piperidin-4-yl)amino)isoindolin-2-yl)piperidine-2,6-dione(100 mg, 80% yield) as a yellow solid. This product was used in the nextstep directly without further purification. MS (ESI) m/z: 343.2 [M+H]⁺.

Step 3. Synthesis of3-(5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of3-(1-oxo-5-(piperidin-4-ylamino)isoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.29 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine(110 mg, 0.29 mmol) in DMSO (5 mL) was added KF (67 mg,1.16 mmol). Theresulting solution was stirred at 120° C. for 5 h, before the reactionwas quenched with water (10 mL) and extracted with ethyl acetate (3×20mL). The combined organic layers were dried over sodium sulfate, andconcentrated. The resulting residue was purified by silica gelchromatography column (DCM/MeOH=12:1) to give3-(5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-1-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(23 mg, 11% yield) as a yellow solid. MS (ESI) m/z: 700.8 [M+H]⁺.

Example 264:2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-N-(1-(6-(6((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)acetamide(TR-213)

Step 1. Synthesis of tert-butyl(R)-(1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)carbamate

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine(189 mg, 0.5 mmol) and tert-butyl azetidin-3-ylcarbamate (86 mg, 0.5mmol) in DMSO (5 mL) was added KF (116 mg, 2 mmol). The resultingsolution was stirred at 120° C. for 5 h, before it was quenched withwater (10 mL) and extracted with ethyl acetate (3×20 mL). The combinedorganic layers were dried over sodium sulfate, and concentrated. Theresulting residue was purified by silica gel chromatography column(DCM/MeOH=10:1) to give tert-butyl(R)-(1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)carbamate(181 mg, 68% yield) as a yellow solid. MS (ESI) m/z: 530.2 [M+H]⁺.

Step 2. Synthesis of3-(1-oxo-5-(piperidin-4-ylamino)isoindolin-2-yl)piperidine-2,6-dione

To a solution of tert-butyl(R)-(1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)carbamate(181 mg, 0.34 mmol) in DCM (5 mL) was added TFA (1 mL) at 0° C. Thereaction was stirred at room temperature for 1 h, beofre solvent wasremoved under vacuum. The resulting residue was washed with diethylether to give3-(1-oxo-5-(piperidin-4-ylamino)isoindolin-2-yl)piperidine-2,6-dione(130 g, 89% yield) as a yellow solid. This product was used in the nextstep directly without further purification. MS (ESI) m/z: 430.2 [M+H]⁺.

Step 3. Synthesis of2-((2-(2,6-dioxopiperidin-yl)-1,3-dioxoisoindolin-5-yl)amino)-N-(1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)acetamide

To a solution of1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carboxylicacid (120 mg, 0,27 mmol) and(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycine (89 mg,0.27 mmol) in N,N-dimethylformamide (10 mL) were added HATU (159 mg,0.54 mmol) and DIEA (108 mg, 0.81 mmol) at 0° C. The mixture was stirredat room temperature for 2 h, beofre the reaction was quenched with water(20 mL) and extracted with ethyl acetate (3×20 mL). The combined organiclayers were dried over sodium sulfate, and concentrated. The resultingresidue was purified by silica gel chromatography (DCM/MeOH=10:1) togive2-((2-(2,6-dioxopiperidin-3yl)-1,3dioxoisoindolin-5-yl)amino)-N-(1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetiden-3-yl)acetamide(97 mg, 46% yield) as a yellow solid. MS (ESI) m/z: 744.0 [M+H]⁺.

Example 265:2-(2,6-Dioxo-3-piperidyl)-5-(2-(4-(6-(6-((2R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2-pyridyl)piperazin-1-yl)ethyl-((4-methoxyphenyl)methyl)amino)isoindoline-1,3-dione(TR-214)

Step 1. Synthesis of 2-((4-methoxyphenyl)methylamino)ethanol

1-(Chloromethyl)-4-methoxy-benzene (8 g, 51.08 mmol) was added to2-aminoethanol (31.201 g, 510.83 mmol) at 0° C. After the resultingreaction mixture was stirred at room temperature for 2 h, the reactionwas quenched with water (100 mL), and extracted with DCM (2×100 mL). Thecombined organic layers were dried over sodium sulfate, andconcentrated. The resulting residue was purified by silica gelchromatography (DCM/MeOH=20:1 to 10:1) to give2-((4-methoxyphenyl)methylamino)ethanol (8 g, 86% yield). MS (ESI) m/z:182.4 [M+H]⁺.

Step 2. Synthesis of2-(2,6-dioxo-3-piperidyl)-5-(2-hydroxyethyl-((4-methoxyphenyl)methyl)amino)isoindoline-1,3-dione

To a solution of 2-((4-methoxyphenyl)methylamino)ethanol (1.09 g, 6.00mmol) and 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (1.38g, 5.00 mmol) in DMSO (20 mL) was added DIPEA (2.58 g, 19.98 mmol) atroom temperature. The reaction mixture was stirred at 120° C. for 16 h,before the mixture was quenched with water (100 mL), and extracted withDCM (50 mL×2). The organic layer was washed with brine (50 mL×2), driedover Na₂SO₄, filtered and concentrated. The resulting residue wasslurried in (petroleum ether/EtOAc=5:1, 50 mL), filtered to give2-(2,6-dioxo-3-piperidyl)-5-(2-hydroxyethyl-((4-methoxyphenyl)methyl)amino)isoindoline-1,3-dione(1.5 g, 69% yield) as a yellow solid. MS (ESI) m/z: 438.4 [M+H]⁺.

Step 3. Synthesis of2-((2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl)-((4-methoxyphenyl)methyl)amino)ethyl4-methylbenzenesulfonate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-(2-hydroxyethyl-((4-methoxyphenyl)methyl)amino)isoindoline-1,3-dione(437 mg, 998.98 umol) in TEA (5 mL) and DCM (5 mL) were added DMAP(122.05 mg, 998.98 nmol) and 4-methylbenzenesulfonyl chloride (285.68mg, 1.50 mmol) at room temperature. After the reaction mixture wasstirred at room temperature for 2 h, the reaction was concentrated andpurified by silica gel chromatography (DCM/MeOH=50:1) to give2-((2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl)-((4-methoxyphenyl)methyl)amino)ethyl4-methylbenzenesulfonate (580 mg, 98% yield). MS (ESI) m/z: 592.4[M+H]⁺.

Step 4. Synthesis of2-(2,6-dioxo-3-piperidyl)-5-(2-(4-(6-(6-((2R)-:2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2-pyridyl)piperazin-1-yl)ethyl-((4-methoxyphenyl)methyl)amino)isoindoline-1,3-dione

To a solution of2-((2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl)-((4-methoxyphenyl)methyl)amino)ethyl4-methylbenzenesulfonate(480.22 mg, 811.69 umol) and6-4-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-piperazin-1-yl-2-pyridyl)imidazo[1,2-b]pyridazine(300 mg, 676.41 umol) in CH₃CN (20 mL) were added K₂CO₃ (560.07 mg, 4.06mmol) and NaI (202.77 mg, 1.35 mmol) at room temperature. After themixture was stirred at 98° C. for 16 h, the reaction was concentratedand purified by silica gel chromatography (DCM/MeOH=50:1 to 20:1) togive 2-(2,6-dioxo-3-piperidyl)-5-(2-(4-(6-(6-((2R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2-pyridyl)piperazin-1-yl)ethyl-((4-methoxyphenyl)methyl)amino)isoindoline-1,3-dione(380 mg, 65% yield) as a yellow solid. MS (ESI) m/z: 864.0 [M+H]⁺.

Example 266: N-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-(6-*6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidine-4-carboxamide(TR-215)

Step 1. Synthesis of(R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidine-4-carboxylicacid

To a solution of piperidine-4-carboxylic acid (38 mg, 0.30 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine(100 mg, 0.26 mmol) in DMSO (8 mL) was added KF (15 mg, 0.26 mmoL) atroom temperature. After it was stirred at 130° C. for 16 h, the,reaction was cooled to room temperature and quenched by H₂O (50 mL). Themixture was extracted with EtOAc (3×10 mL). The combined organic layerswere concentrated and purified by reverse-phase chromatography to givethe desired product (65 mg, 52% yield) as a light yellow solid. MS (ESI)m/z: 487.2 [M+H]⁺.

Step 2. Synthesis of(R)1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidine-4-carbonylchloride

To a mixture of(R)-1-(6(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidine-4-carboxylicacid (65 mg, 0.13 mmol) and DMF (3 mg, 0.04 mmol) in DCM (10 mL) wasadded oxalyl chloride (330 mg, 2.6 mmoL) at room temperature. After itwas stirred at reflux for 2 h, the reaction was concentrated and useddirectly in the next step without further purification (60 mg, 92%yield) as a light yellow solid.

Step 3. Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3yl)pyridin-2-yl)piperidine-4-carboxamide

To a mixture of 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(35 mg, 0.13 mmol) in THF (5 mL) was added(R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidine-4-carbonyl chloride(60 mg, 0.12 mmoL) at room temperature. After it was stirred at roomtemperature for 1h, the mixture was concentrated and purified byreverse-phase chromatography to give the desired productN-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidine4-carboxamide(12 mg, 13% yield) as a light yellow solid. MS (ESI) m/z: 742.3 [M+H]⁺.

Example 267:3-[4-[2-[4-[6-[6-[(2R)-2-(3-Fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]piperazin-1-yl]ethylamino]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(TR-216)

Step 1. Synthesis of 2-(methylamino)-3-nitrobenzoic acid

To a solution of 2-fluoro-3-nitrobenzoic acid (20 g, 0.108 mol) andmethanamine hydrochloride (8.7 g, 0.129 mol) int EtOH (200 mL) was addedDIEA (70 g, 0.54 mol) at room temperature. After the reaction mixturewas stirred at 80° C. overnight, the reaction was cooled down to roomtemperature. After concentration, the resulting residue was diluted withwater (100 mL) and adjusted the pH to 3 with cone. HCl, and extractedwith EtOAc (2×150 mL). The combined organic layers were washed withbrine twice, dried with sodium sulfate, filtered and concentrated togive crude 2-(methylamino)-3-nitrobenzoic acid (21 g, 100% yield) as ayellow solid. This product was used in the next step directly withoutfurther purification. MS (ESI) m/z: 197.3 [M+H]⁺.

Step 2. Synthesis of1-methyl-7-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

To a solution of 2-(methylamino)-3-nitrobenzoic acid (24 g, 0.122 mol)in t-BuOH (300 mL) were added DIPEA (31 g, 0.244 mol) and DPPA (37 g,0.134 mol) at room temperature. After the reaction mixture was stirredat 90° C. for 16 h, the reaction solution was concentrated. Theresulting residue was triturated with water (500 ml), filtered andwashed with EtOAc. The soild was collected and dried to give1-methyl-7-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (22 g, 93% yield)as a yellow solid. MS (ESI) m/z: 194.1 [M+H]⁺.

Step 3. Synthesis of3-(3-methyl-5-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a suspension of NaH (48 mg, 1.20 mmol) in DMF (5 mL) was added3-methyl-5-nitro-1H-benzimidazol-2-one (193 mg, 999.18 umol) at 0° C.The reaction mixture was stirred at 0° C. for 0.5 h, before a slolutionof 3-bromopiperidine-2,6-dione (383.70 mg, 2.00 mmol) in DMF (5 mL) wasadded dropwise. After the completion of addition, the reaction mixturewas stirred at 80° C. for 2 h. After concentration, the reaction waspurified by prep-HPLC to give3-(3-methyl-5-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (80 mg,26% yield) as a black solid. MS (ESI) m/z: 305.3 [M+H]⁺.

Step 4. Synthesis of3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (80 mg,262.93 nmol) in MeOH (10 mL) and THF (10 mL) was added Pd/C (20 mg) atroom temperature. After the reaction mixture was stirred at roomtemperature for 1h under hydrogen atmosphere, the reaction was filteredand concentrated to give3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (70 mg,97% yield) as a brown solid. This product was used in the next stepdirectly without further purification. MS (ESI) m/z: 275.3 [M+H]⁺.

Step 5. Synthesis of3-[4-[2-[4-[6-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]piperazin-1-yl]ethylamino]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of2-[4-[6-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]piperazin-1-yl]acetaldehyde(61.96 mg, 127.61 umol) and3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (35 mg,127.61 umol) in DMF (10 mL) were added TMSCl (41.35 mg, 382.83 nmol) andNaBH₄ (9.70 mg, 255.22 umol) at 0° C. After the reaction mixture wasstirred at 0° C. for 4 h, the rection was warmed to room temperature andstirred for 16 h. After concentration, the reaction was purified byprep-HPLC to give the product with some impurities. The crude materialwas further purified by prep-TLC (DCM/MeOH=15:1) to give3-[4-[2-[4-[6-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]piperazin-1-yl]ethylarnino]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(14 mg, 15% yield) as a white solid. MS (ESI) m/z: 744.9 [M+H]⁺.

Example 268:3-[4-[3-[4-[6-[6-[(2R)-2-(3-Fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]piperazin-1-yl]propylamino]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(TR-217)

To a solution of3-[4-[6-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]piperazin-1-yl]propanal(54.64 mg, 109.38 umol) and3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (30 mg,109.38 umol) in DMF (5 mL) were added TMSCl (41.35 mg, 328.14 umol) andNaBH₄ (8.31 mg, 218.76 umol) at 0° C. After the reaction mixture wasstirred at 0° C. for 4 h, the reaction was warmed to room temperatureand stirred for 16 h. After concentration, the reaction was purified byprep-HPLC to give the crude product, which was further purified a byprep-TLC/DCM/MeOH=15:1) togive3-[4-[3-[4-[6-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]piperazin-1-yl]propylamino]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6dione (10 mg, 12% yield) as a white solid. MS (ESI) m/z: 759.0 [M+H]⁺.

Example 269:3-(5-(((1-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-218)

Step 1. Synthesis of tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)methyl)piperidine-1-carboxylate

To a solution of 3-(5-amino-1-oxoisoindolin-2-yl) piperidine-2,6-dione(130 mg, 0.5 mmol) in dichloromethane (10 mL) and AcOH (2.0 mL) wereadded tert-butyl4-formylpiperidine-1-carboxate (130 mg,1.0 mmol) andBH₃/THF (1 M, 0.5 ml). After the mixture was stirred at room temperaturefor 16 h, the reaction was quenched with water (20 mL) and extractedwith ethyl acetate (3×20 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated to give tert-butyl(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)methyl)piperidine-1-carboxylate(230 mg, crude) as a green solid. This crude product was used in thenext step directly without further purification. MS (ESI) m/z: 457.3[M+H]⁺.

Step 2. Synthesis of3-(1-oxo-5-((piperidin-4-ylmethyl)amino)isoindolin-2-yl)piperidine-2,6-dione

To a solution of tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)methyl)piperidine-1-carboxylate(230 mg, crude) in DCM (10 mL) was added TFA (2 mL) at 0° C. After thereaction mixture was stirred at room temperature for 16 h, the solventwas removed under vacuum. The resulting residue was washed with diethylether to give3-(1-oxo-5-((piperidin-4-ylmethyl)amino)isoindolin-2-yl)piperidine-2,6-dione(200 mg, crude) as a yellow solid. This product was used in the nextstep directly without further purification. MS (ESI) m/z: 357.3 [M+H]⁺.

Step 3. Synthesis of3-(5-(((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of3-(1-oxo-5-((piperidin-4-ylmethyl)amino)isoindolin-2-yl)piperidine-2,6-dione(200 mg, crude) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine(88 mg, 0,23 mmol) in DMSO (5 mL) was added KF (2.70 mg, 0.92 mmol). Theresulting solution was stirred at 120° C. for 5 h, before the reactionwas quenched with water (10 mL) and extracted with ethyl acetate (3×10mL). The combined organic layers were dried over sodium sulfate, andconcentrated. The resulting residue was purified by silica gel column(DCM/MeOH=10:1) to give3-(5-(((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(14 mg, 8% yield) as a yellow solid. MS (ESI) m/z: 714.8 [M+H]⁺.

Example 270:3-(5-((1-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(TR-219)

Step 1. Synthesis oftert-butyl3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethynyl)azetidine-1-carboxylate

To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione(136 mg, 0.42 mmol) DMF (5 mL) were added TEA(170 mg, 4.2 mmol), CuI (8mg, 0.04 mmol), Pd(dppf)Cl₂ (31 mg, 0.04 mmol), andtert-butyl3-ethynylazetidine-1-carboxylate (100 mg, 0.42mmol). Thereaction mixture was stirred at 80° C. for 12 h. Then the resultingblack mixture was diluted with ethyl acetate (20 mL), washed with brine(3×20 mL). The organic layer was dried over sodium sulfate, filtered,and concentrated. The resulting residue was purified by silica gel flashchromatography (petroleum/ethyl acetate=3:7) to givetert-butyl3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethynyl)azetidine-1-carboxylate(130 mg, 73% yield) as a brown solid. MS (ESI) m/z: 424.2 [M+H]⁺.

Step 2. Synthesis of3-(5-(azetidin-3-ylethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of tert-butyl3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethynyl)azetidine-1-carboxylate(130 mg, 0.30 mmol) in DCM (5 mL) was added TFA (1 mL) at 0° C. Afterthe reaction was stirred at room temperature for 1 h, the solvent wasremoved under vacuum. The residue was washed with diethyl ether to givecrude3(5-(azetidin-3-ylethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (86mg, 89% yiled) as a yellow solid. This product was used in the next stepdirectly without further purification. MS (ESI) m/z: 324.2 [M+H]⁺.

Step 3. Synthesis3-(5-((1-(6-(6-((R)2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of3-(5-(azetidin-3-ylethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(86 mg, 0.26 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine(60 mg, 0.26 mmol) in DMSO (5 mL) was added KF (77 mg, 1.04 mmol). Theresulting solution was stirred at 120° C. for 5 h, before the reactionwas quenched with water (20 mL) and extracted with ethyl acetate (3×20mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated. The resulting residue was purified by silicagel column (DCM/MeOH=10:1) to give3-(5-((1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)azetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(47 mg, 26% yield) as a yellow solid. MS (ESI) m/z: 681.2 [M+H]⁺.

Example 271:3-(5-((2-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(TR-220)

Step 1. Synthesis of 2-(methylamino)-4-nitro-benzoic acid

To a solution of 2-fluoro-4-nitro-benzoic acid (37 g, 199.88 mmol) andmethanamine hydrochloride (12.42 g, 399.76 mmol) in NMP (300 mL) wasadded DIPEA (103.33 g, 799.53 mmol) at room temperature. The reactionmixture was stirred at 120° C. for 48 h. After the reaction was cooleddown to room temperature, the reaction was quenched with water (100 mL),and the pH was adjusted to 3 with conc. HCl. The resulting solid wasfiltered and dried to give crude 2-(methylamino)4-nitro-benzoic acid (38g, 97% yield) as a yellow solid. This product was used in the next stepdirectly without further purification. MS (ESI) m/x: 197.3 [M+H]⁺.

Step 2. Synthesis of 3-methyl-5-nitro-1H-benzimidazol-2-one

To a solution of 2-(methylamino)-4-nitro-benzoic acid (38 g, 193.72mmol) in t-BuOH (30 mL) were added DIPEA (75.11 g, 581.16 mmol) and DPPA(63.93 g, 232.46 mmol) at room temperature. Then the reaction mixturewas stirred at 90° C. for 16 h. After the reaction was cooled down toroom temperature, the mixture was filtered and resuting solid was driedto give crude 3-methyl-5-nitro-1H-benzimidazol-2-one (33 g, 88% yield)as a yellow solid. This product was used in the next step directlywithout further purification. MS (ESI) m/z: 194.1 [M+H]⁺.

Step 3. Synthesis of3-(5-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a suspension of NaH (48 mg, 1.20 mmol) in DMF (5 mL) was added1-methyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (193 mg, 999.18umol) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h,before a solution of 3-bromopiperidine-2,6-dione (383.70 mg, 2.00 mmol)in DMF (5 mL) was added dropwise. After the completion of addition, thereaction mixture was stirred at 80° C. for 2 h. After the rection iscooled down to room temperature, the reaction was concentrated and theresulting residue was purified by prep-HPLC to give3-(5-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(80 mg, 26% yield) as a black solid. MS (ESI) m/z: 305.3 [M+H]⁺.

Step 4. Synthesis of 3-(5-amino-3-methyl-2-oxo-2,3-dihydro-4H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of3-(5-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(80 mg, 262.93 umol) in MeOH (10 mL) and THF (10 mL) was added Pd/C (20mg) at room temperature. After the reaction mixture was stirred at roomtemperature for 1 h under hydrogen atmosphere, the reaction was filteredand the filtrate was concentrated to give crude3-(5-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(70 mg, 97% yield) as a brown solid. This product was used in the nextstep directly without further purification. MS (ESI) m/z: 275.3 [M+H]⁺.

Step 5. Synthesis of3-(5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetaldehyde(57 mg, 0.12 mmol) in DMF (3 ml) were added3-(5-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(31 mg, 0.11 mmol), TMSCl (39 mg, 0.36 mmol) and NaBH₄ (9 mg, 0.24mmol). The reaction mixture was stirred at 0° C. for 48 h. After thereaction was concentrated, the resulting residue was purified byprep-HPLC to give3-(5-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (7 mg,8% yield) as a yellow solid. MS (ESI) m/z: 744.8 [M+H]⁺.

Example 272:3-(5-((3-(4-(6-((R)-2(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(TR-221)

To a solution of(R)-3-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propanal(132.92 mg, 266.06 umol) and3-(5-amino-3methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(82 mg, 298.97 umol) in DMF (10 mL) were added TMSCl (86.20 mg, 798.17umol) and NaBH₄ (20.22 mg, 532.11 umol) at 0° C. After the reactionmixture was stirred at 0° C. for 1.5 h, the reaction was warmed to roomtemperature and stirred for 16 h. After concentration, the mixture waspurified by prep-HPLC to give a crude product, which was furtherpurified by prep-TLC(DMC/MeOH=10:1) to give3-(5-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)amino)3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(17 mg, 8% yield) as a white solid. MS (ESI) m/z: 759.0 [M+H]⁺.

Example 273:2-(2,6-Dioxopiperidin-3-yl)-5-(3-((4-(3-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-pyrrol-1-yl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione(TR-222)

Step 1. Synthesis of tert-butyl(R)-3-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

To a solution of(R)-3-bromo-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine(360 mg, 996.65 umol) andtert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate(294.19 mg, 996.65 umol) in dioxane (10 mL) and H₂O (5 mL) were addedK₂CO₃ (275.07 mg, 1.99 mmol) and Pd(dppf)C₂ (72.85 mg, 99.66 umol) atroom temperature under N₂. After the reaction mixture was stirred at100° C. for 4 h, the reaction was concentrated and purified by silicagel chromatography (DCM/MeOH=30:1) to give tert-butyl(R)-3-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(440 mg, 98% yield) as a black solid. MS (ESI) m/z: 451.0 [M+H]⁺.

Step 2. Synthesis of(R)-3-(2,5-dihydro-1H-pyrrol-3-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazinehydrochloride

To a solution of tert-butyl(R)-3-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(450 mg, 1.00 mmol) in DCM (5 mL) was added HCl/dioxane (4 mL) at roomtemperature. The reaction mixture was stirred at room temperature for 2h, before it was concentrated to give crude(R)-3-(2,5-dihydro-1H-pyrrol-3-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazinehydrochloride (350 mg, 100% yield) as solid (HCl salt). This product wasused in the next step directly without further purification. MS (ESI)m/z: 350.6 [M+H]⁺.

Step 3. Synthesis of benzyl(R)-4-(3-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,5-dihydro-1H-pyrrol-1-yl)piperidine-1-carboxylate

To a solution of3-(2,5-dihydro-1H-pyrrol-3-yl)-6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine(600 mg, 1.72 mmol) and benzyl4-methylsulfonyloxypiperidine-1-carboxylate (2.15 g, 6.87 mmol) in CH₃CN(20 mL) and DMF (20 mL) were added NaI (514.79 mg, 3.43 mmol) and K₂CO₃(1.42 g, 10.30 mmol). The reaction mixture was stirred at 100° C. for 16h, before it was concentrated and purified by silica gel chromatography(DCM/MeOH=20:1) to give benzyl(R)-4-(3-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,5-dihydro-1H-pyrrol-1-yl)piperidine-1-carboxylate(230 mg, 24% yield). MS (ESI) m/z: 567.9 [M+H]⁺.

Step 4. Synthesis of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(1-(piperidin-4-yl)-2,5-dihyro-1H-pyrrol-3-yl)imidazo[1,2-b]pyridazine

To a solution of benzyl(R)-4-(3-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,5-dihydro-1H-pyrrol-1-yl)piperidine-1-carboxylate(200 mg, 352.94 umol) AcOH (10 mL) was added HBr (5 mL) at roomtemperature. The reaction mixture was stirred at 50° C. for 16 h, beforethe reaction was concentrated. The resulting residue was diluted withwater and pH value was adjusted to 9 with aq. NaHCO₃. The resultingaquoes mixture was extracted with DCM (2×30 mL). The combined organiclayers were washed with brine (2×20 mL), dried over Na₂SO₄, filtered,and concentrated. The resulting residue was purified by prep-TLC(DCM/MeOH=10:1) to give(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(1-(piperidin-4-yl)-2,5-dihydro-1H-pyrrol-3-yl)imidazo[1,2-b]pyridazine(120 mg, 79% yield) as a white solid. MS (ESI) m/z: 433.6 [M+H]⁺.

Step 5. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(3-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-pyrrol-1-yl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(1-(piperidin-4-yl)-2,5-dihydro-1H-pyrrol-3-yl)imidazo[1,2-b]pyridazine(60 mg, 138.72 umol) and(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl4-methylbenzenesulfonate (69.01 mg, 138.72 umol) in CH₃CN (10 mL) wereadded NaI (41.58 mg, 277.43 umol) and K₂CO₃ (114.86 mg, 832.30 umol) atroom temperature. After the mixture was stirred at 95° C. for 16 h, thereaction was concentrated and purified by prep-TLC (DCM/MeOH=10:1) togive crude product, then purified again by prep-TLC (DCM/MeOH=20:1) togive2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(3-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1H-pyrrol-1-yl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione(17 mg, 16% yield) as a yellow solid. MS (ESI) m/z: 757.0 [M+H]⁺.

Example 274:3-((S)-5-(3-(3(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-diode(TR-223)

Step 1. Synthesis of3-(3-((5S)-3-(2,6-dioxopiperidin-3-yl)-2-oxooxazolidin-5-yl)phenyl)prop-2-yn-1-yl4-methylbenzenesulfonate

To a solution of3-((S)-5-(3-(3-hydroxyprop-1-yn-1-yl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione(30 mg, 0.1 mmol) in dichloromethane (2 mL) were added TsCl (36 mg, 0.18mmol) and DMAP (21.9 mg, 0.2 mmol). After the mixture was stirred atroom temperature for 4 h, the reaction was quenched with water (20 mL)and extracted with ethyl acetate (3×20 mL). The combined organic layerswere dried over sodium sulfate, filtered, and concentrated. Theresulting residue was purified by silica gel chromatography(MeOH/DCM=1:10) to give3-(3-((5S)-3-(2,6-dioxopiperidin-3-yl)-2-oxooxazolidin-5-yl)phenyl)prop-2-yn-1-yl4-methylbenzenesulfonate(22 mg, 70% yield) as a yellow solid. MS (ESI) m/z: 348.3 [M+H]⁺.

Step 2. Synthesis of3-((S)-5-(3-(3-(4-(6-(6-((S)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione

To a solution of3-(3-((5S)-3-(2,6-dioxopiperidin-3-yl)-2-oxooxazolidin-5-yl)phenyl)prop-2-yn-1-yl-4-methylbenzenesulfonate(22 mg, 0.06 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(26 mg, 0.06 mmol) in acetonitrile (2 mL) were added potassium carbonate(13 mg, 0.12 mmol) and sodium iodide (8 mg, 0.2 mmol). The reactionmixture was stirred at 80° C. for 2 h, before the reaction wasconcentrated and purified by silica gel chromatography (DCM/MeOH=10:1)to give3-((S)-5-(3-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione(25 mg, 38% yield) as a yellow solid. MS (ESI) m/z: 754.8 [M+H]⁺.

Example 275:3-((S)-5-(4-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazoi[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione(TR-224)

Step 1. Synthesis of3-(4-((5S)-3-(2,6-dioxopiperidin-3-yl)-2-oxooxazolidin-5-yl)phenyl)prop-2-yn-1-yl4methylbenzenesulfonate

To a solution of3-((S)5-(4-(3-hydroxyprop-1-yn-1-yl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione(40 mg, 0.12 mmol) in dichloromethane (2 mL) were added TsCl (68 mg,0.35 mmol) and DMAP (76 mg, 0.6 mmol) at room temperature. The reactionmixture was stirred at room temperature for 4 h, before the reaction wasquenched with water (20 mL) and extracted with ethyl acetate (3×20 mL).The combined organic layers were dried over sodium sulfate, filtered,and concentrated. The resulting residue was purified by silica gelchromatography (MeOH/DCM=1:10) to give3-(4-(5S)-3-(2,6-dioxopiperidin-3-yl)-2-oxooxazolidin-5-yl)phenyl)prop-2-yn-1-yl4-methylbenzenesulfonate (30 mg, 71% yield) as a yellow solid. MS (ESI)m/z: 483.3 [M+H]⁺.

Step 2. Synthesis of3-((S)5-(4-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)-phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione

To a solution of3-(4-((5S)-3-(2,6-dioxopiperidin-3-yl)-2-oxooxazolidin-5-yl)phenyl)prop-2-yn-1-yl-4-methylbenzenesulfonate(30 mg, 0.08 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,12-b]pyridazine(27 mg,0.08mmol) in acetonitrile (3 mL) were added potassium carbonate(17 mg, 0.16 mmol) and sodium iodide (9 mg, 0.08 mmol). The reactionmixture was stirred at 80° C. for 2 h, before it was concentrated andpurified by silica gel chromatography (DCM/MeOH=10:1) to give3-((S)-5-(4-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione (17 mg, 36% yield) as a yellow solid. MS(ESI) m/z: 754.8 [M+H]⁺.

Example 276:2-(2,6-Dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)inlidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)isoindoline-1,3-dione(TR-225)

Step 1. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione

A solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione(100 mg, 0.362 mmol), pyrrolidin-3-ylmethanol (55 mg, 0.543 mmol) andDIEA (234 mg, 1.81 mmol) in NMP(5 mL) was stirred at 120° C. for halfhour. After the reaction was cooled down to room temperature, theresulting solution was diluted with EtOAc (100 mL), washed with brinetwice, dried over sodium sulfate and concentrated to give the crude2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione(140 mg, 108% yield) as a colorless oil. This product was used in thenext step directly without further purification. MS (ESI) m/z: 358.5[M+H]⁺.

Step 2. Synthesis of1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-)pyrrolidine-3-carbaldehyde

A mixture of2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione(140 mg, 0.39 mmol) and Dess-Martin oxidant (826 mg,1.95 mmol) in DCM (5mL) and DMF (2 mL) was stirred at 40° C. for 20 mins. After the reactionwas cooled down to room temperature, the reaction mixture was dilutedwith brine (100 mL) and EtOAc (100 mL). The organic phase was washedwith brine twice, dried over sodium sulfate, and concentrated. Theresulting residue was purified by silica gel chromatography(DCM/MeOH=15:1) to afford1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde(80 mg, 58% yield) as a yellow solid. MS (ESI) m/z: 356.7 [M+H]⁺.

Step 3. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)isoindoline-1,3-dione

To a solution of1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde(80 mg, 0.225 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazinehydrochloride (107 mg, 0.225 mmol) in DCE (3 ml) and THF (3 mL) wereadded DIEA (30 mg, 0.225 mmol) and titanium tetraisopropanolate (639 mg,2.25 mmol). After the reaction mixture was stirred at 40° C. for 0.5 h,sodium cyanoborohydride (140 mg, 2.25 mmol) was added. The resultingreaction mixture was stirrted at room temperature for 1 h, before thereaction mixture was diluted with DCM/MeOH (10:1, 150 mL) and saturatedNaHCO₃ (20 ml). After being stirred for 5 mins, the mixture was filteredthrough celite. The filtrate was washed with brine twice, dried oversodium sulfate, filtered and concentrated. The resulting residue waspurified by prep-HPLC to give2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)isoindoline-1,3-dione(9.6 mg, 6% yield) as a yellow solid. MS (ESI) m/z:784.0 [M+H]⁺.

Example 277:2-(2,6-Dixopiperidin-3-yl)-5-(4-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione(TR-226)

Step 1. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione

A solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione(130 mg, 0.471 mmol), piperidin-4-ylmethanol (81 mg, 0.706 mmol) andDIEA (303 mg, 2.355 mmol) in NMP (5 ml) was stirred at 120° C. for 0.5h. After the reaction was cooled down to room tempeature, the resultingsolution was diluted with EtOAc (100 mL), washed with brine twice, driedover sodium sulfate, filtered and concentrated to give the crude product2-(2,6-diaxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)-isoindoline-1,3-dione(200 mg, 114% yield) as a colorless oil. This product was used in thenext step directly without further purification. MS (ESI) m/z: 372.5[M+H]⁺.

Step 2. Synthesis of1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde

A mixture of2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione(200 mg, 0.539 mmol) and Dess-Martin oxidant (1.14 mg, 2.69 mmol) in DCM(5 ml) and DMF (2 ml) was stirred at 40° C. for 20 mins. After thereaction was cooled down to room temperature, the reaction mixture wasdiluted with brine (100 mL) and EtOAc (100 mL). The organic phase waswashed with brine twice, dried, filtered and concentrated. The resultingresidue was purified by silica gel chromatography (DCM/MeOH=15:1) toafford1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde(50 mg, 25% yield) as a yellow solid. MS (ESI) m/z: 370.5 [M+H]⁺.

Step 3. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

To a solution of1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde(50 mg, 0.135 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazinehydrochloride (51 mg, 0.135 mmol) in DCE (6 mL) were added DIEA (18 mg,0.135 mmol) and titanium tetraisopropanolate (383 mg, 1.35 mmol). Thereaction mixture was stirred at 40° C. for 0.5 h, before sodiumcyanoborohydride (140 mg, 2.25 mmol) and MeOH (3 ml) was added. Afterthe reaction mixture was stirrted at room temperature for 1 h, thereaction mixture was diluted with DCM/MeOH (10:1, 150 mL) and saturatedaqueous NaHCO₃ (20 ml), After being stirred for 5 mins, the mixture wasfiltered through celite. And the filtrate was washed with brine twice.The organic layer was dried over sodium sulfate, filtered andconcentrated. The resulting residue was purified by prep-HPLC to give2-(2,6-dioxopiperidin-3-yl)-5-4((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione(8.6 mg, 8% yield) as a yellow solid. MS (ESI) m/z: 798.0 [M+H]⁺.

Example 278:3-(3-(2-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(TR-227)

Step 1. Synthesis of 2-((2-nitrophenyl)amino)ethan-1-ol

To a solution of 1-fluoro-2-nitrobenzene (10 g, 70.9 mmol) in EtOH (80mL) were added K₂CO₃ (11.7 g, 85.04 mmol) and 2-aminoethan-1-ol (13.0 g,212.6 mmol). The reaction was stirred at reflux for 12 h. After thereaction was cooled to room temperature, water and ethyl acetate wereadded. The organic phase was separated, dried over anhydrous sodiumsulfate, filtered and concentrated. The resulting crude product wastriturated with EtOAc/petroleum ether (20 mL, 10:1) to give2-((2-nitrophenyl)amino)ethan-1-ol (11 g, 85% yield) as a yellow solid.MS (ESI) m/z: 18.4 [M+H]⁺.

Step 2. Synthesis of 2((2-aminophenyl)amino)ethan-1-ol

To a solution of 2((2-nitrophenyl)amino)ethan-1-ol (7.0 g, 38.5 mmol) inEtOH (30 mL) was added 10% Pd/C (0.5 g). The reaction mixture wasstirred at room temperature overnight under hydrogen atmosphere. Afterfiltration through a celite cup, the filtrate was concentrated to givecrude 2-((2-aminophenyl)amino)ethan-1-ol (5.9 e, 99% yield). Thisproduct was used in the next step directly without further purification.MS (ESI) m/z: 153.3 [M+H]⁺.

Step 3. Synthesis of-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzene-1,2-diamine

To a solution of 2((2-aminophenyl)amino)ethan-1-ol (1.0 g, 6.58 mmol) inDCM (20 mL) were added imidazole (671 mg, 9.87 mmol) andtert-butyldimethylsilyl chloride (1.19 g, 7.89 mmol). After the mixturewas stirred at room temperature for 15 h, the reaction was quenched withwater and extracted with ethyl acetate (50 mL). The organic layer waswashed with water twice, saturated brine, dried over sodium sulfate,filtered and concentrated. The resulting residue was triturated withpetroleum ether/EtOAc (20 mL/2 mL) to giveN^(l)-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzene-1,2-diamine (11 g,63% yield) as a pale solid. MS (ESI) m/z: 268.0 [M+H]⁺.

Step 4. Synthesis of1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

To a solution ofN^(l)-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzene-1,2-diamine (1.7g,6.39 mmol), in THF (25 mL) was added N,N′-carbonyldiimidazole (2.07 g,12.78 mmol) under N₂. The reaction mixture was stirred at roomtemperature for 4 h, before the solvent was removed under vacuum. Theresulting residue was recrystallized from methanol and n-hexane to give1-(2-((tert-butyldimethylsiyl)oxy)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one(1.4 g, 75% yield) as a white solid. MS (ESI) m/z: 293.3 [M+H]⁺.

Step 5. Synthesis of3-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a stirred solution of1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one(458 mg, 1.57 mmol) in DMF (2 mL) was added NaH (69.08 mg, 60% w/wdispersed into mineral oil, 1.73 mmol) at 0° C. under N₂. After thereaction mixture was stirred for 20 min at 0° C., a solution of3-bromopiperidine-2,6-dione (150 mg, 0.79 mmol) in DMF (0.5 mL) wasadded dropwise at 0° C. After the resulting mixture was stirred foradditional 3 h at room temperature, the reaction was quenched with AcOH(0.5 mL) and concentrated under reduced pressure. The residue waspurified by silica gel chromatography column (petroleum ether/EtOAc=4:1)to afford3-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(132 mg, 21% yield) as a white solid. MS (ESI) m/z: 404.9 [M+H]⁺.

Step 6. Synthesis of3-(3-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of3-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(130 mg, 0.32 mmol) in tetrahydrofuran (10 mL) was added tetra-n-butylammonium fluoride (168.71 mg, 0.65 mmol). The mixture was stirred atroom temperature for 1 h. After removal of the solvent, the resultingresidue was purified by silica gel chromatography column(hexane/EtOAc=1:1) to afford3-(3-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(83 mg, 90% yield) as a white solid. MS (ESI) m/z: 290.3 [M+H]⁺.

Step 7. Synthesis of2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl4-methylbenzenesulfonate

To a solution of3-(3-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(83 mg, 0.29 mmol) in dry CH₂Cl₂ (5 mL) were added p-toluensulfonylchloride (82.1 mg, 0.43 mmol), 4-dimethylaminopyridine (12 mg, 0.1 mmol)and Et₃N (279 mL, 2 mmol) at 0° C. After the reaction mixture wasstirred at room temperature for 24 h. the reaction was quenched withwater, and extracted with DCM. The organic layer was washed with brineand dried over MgSO₄, filtered and concentrated. The resulting residuewas purified by prep-TLC (petroleum ether/EtOAc=2:1) to afford2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl4-methylbenzenesulfonate (60 mg,47% yield) as a white solid. MS (ESI)m/z: 444.5 [M+H]⁺.

Step 8. Synthesis of3-(3-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl4-methylbenzenesulfonate (60 mg, 0.14 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(67 mg, 0.14 mmol) in DMF (2 mL) was added DIEA (89.6 mg, 0.70 mmol).The reaction mixture was stirred at 60° C. for 12 h. After the reactionwas cooled down to room temperature, the solution was quenched withwater and extracted with EtOAc. The organic layer was washed with brineand dried over MgSO₄, filtered and concentrated. The resulitng residuewas purified by prep-TLC to give3-(3-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(17 mg, 17% yield) as a white solid. MS (ESI) m/z: 715.9 [M+H]⁺.

Example 279:3-(3-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(TR-228)

Step 1. Synthesis of 3-((2-nitrophenyl)amino)propan-1-ol

To a solution of 1-fluoro-2-nitrobenzene (10 g, 70.87 mmol) in EtOH (80mL) were added K₂CO₃ (11.7 g, 85.04 mmol) and 3-aminopropan-1-ol (15.9g, 212.6 mmol). After the reaction was stirred at reflux for 12 h, thereaction was cooled to room temperature, quenched with water, anddiluted with ethyl acetate. The organic phase was separated, dried overanhydrous sodium sulfate, filtered and concentrated. The resulting crudeproduct was triturated with EtOAc/petroleum ether (20 mL, 10:1) to give3-((2-nitrophenyl)amino)propan-1-ol (11.1 g, 80% yield) as a yellowsolid. MS (ESI) m/z: 197.3 [M+H]⁺.

Step 2. Synthesis of 3((2-aminophenyl)amino)propan-1-ol

To a solution of 3-((2-nitrophenyl)amino)propan-1-ol (7.0 g, 38 5 mmol)in EtOH (30 mL) was added 10% Pd/C (1.0 g). The reaction mixture wasstirred at room temperature overnight under hydrogen atmosphere. Afterthe catalyst wsa filtered off through a celite cup, the filtrate wasconcentrated to give crude 3((2-aminophenyl)amino)propan-1-ol (8.82 g,99% yield). This product was used in the next step directly withoutfurther purification. MS (ESI) m/z: 168.3 [M+H]⁺.

Step 3. Synthesis ofN^(l)-(3-((tert-butyldimethylsilyl)oxy)propyl)benzene-1,2-diamine

To a solution of 3-((2-aminophenyl)amino)propan-1-ol (3.0g, 18.07 mmol)in DCM (25 mL) were added imidazole (1.85 g, 27.1 mmol) andtert-butyldimethylsilyl chloride (3.27 g, 21.68 mmol). The mixture wasstirred at room temperature for 15 h, before the reaction was quenchedwith water and extracted with ethyl acetate (50 mL). The organic layerwas washed with water twice and saturated aqueous brine, dried oversodium sulfate, filtered and concentrated. The residue was trituratedwith petroleum ether/EtOAc (40 mL/5 mL) to giveN^(l)-(3-((tert-butyldimethylsilyl)oxy)propyl)benzene-1,2-diamine (5.6g, 74% yield) as a pale solid. MS (ESI) m/z: 282.0 [M+H]⁺.

Step 4. Synthesis of1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

To a solution ofN^(l)-(3-((tert-butyldimethylsilyl)oxy)propyl)benzene-1,2-diamine (5.6g, 18.4 mmol), in THF (50 mL) was added N,N′-carbonyldiimidazole (5.97g, 36.86 mmol) under N₂. The reaction mixture was stirred at roomtemperature for 4 h, at which time the solvent was removed under vacuum.The resulting residue was recrystallized from methanol and n-hexane togive1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one(5 g, 88% yield) as a white solid. MS (ESI) m/z: 308.0 [M+H]⁺.

Step 5. Synthesis of3-(3-(3-((tert-butyldimethylsilyl(oxy)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a stirred solution of1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1,3-dihydro-2H-berizo[d]imidazol-2-one(465 mg, 1.57 mmol) in DMF (2 mL) was added NaH (69.08 mg, 60% w/wdispersed into mineral oil, 1.73 mmol) at 0° C. under N₂. After thereaction mixture was stirred for 20 min at 0° C., a solution of3-bromopiperidine-2,6-dione (150 mg, 0.79 mmol) in DMF (0.5 mL) wasadded dropwise at 0° C. The resulting mixture was stirred for additional3 h at room temperature, before the reaction was quenched with AcOH (0.5mL) and concentrated under reduced pressure. The resulting residue waspurified by silica gel chromatography column (petroleum ether/EtOAc=4:1)to afford3-(3-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(150.5 mg, 23% yield) as a white solid. MS (ESI) m/z: 418.9 [M+H]⁺.

Step 6. Synthesis of3-(3-(3-hydroxypropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of3-(3-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(300 mg, 0.74 mmol) in tetrahydrofuran (10 mL) was added tetra-n-butylammonium fluoride (384.5 mg, 1.47 mmol). The mixture was stirred at roomtemperature for 1 h. After removal of the solvent, the resulting residuewas purified by silica gel chromatography column (hexane/EtOAc=1:1) toafford3-(3-(3-hydroxypropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(83 mg, 90% yield) as a white solid. MS (ESI) m/z: 304.4 [M+H]⁺.

Step 7. Synthesis of3-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl4-methylbenzenesulfonate

To a solution of3-(3-(3-hydroxypropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(220 mg, 0.66 mmol) in dry CH₂Cl₂ (5 mL) were added p-toluensulfonylchloride (188 mg, 0.99 mmol), 4-dimethylaminopyridine (12 mg, 0.1 mmol)and Et₃N (279 mL, 2 mmol) at 0° C. After the reaction mixture wasstirred at room temperature for 24 h, the reaction was quenched withwater, and extracted with DCM. The organic layer was washed with brineand dried over MgSO₄, filtered and concentrated. The resulting residuewas purified by prep-TLC (petroleum ether/EtOAc=2:1) to afford3-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl4-methylbenzenesulfonate (150 mg, 50% yield) as a white solid. MS (ESI)m/z: 458.5 [M+H]⁺.

Step 8. Synthesis of3-(3-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of3-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl4-methylbenzenesulfonate (70 mg, 0.16 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(76.6 mg, 0.16 mmol) in DMF (2 mL) was added DIEA (89.6 mg, 0.70 mmol).The reaction mixture was stirred at 60° C. for 12 h. After the reactionwas cooled down to room temperature, the reaction was quenched withwater and extracted with EtOAc. The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated. The resulting residue waspurified by prep-TLC to give3-(3-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(22 mg, 17% yield) as a white solid. MS (ESI) m/z: 729.9 [M+H]⁺.

Example 280:3-((S)-5-(4-((4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione(TR-229)

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazinehydrochloride (40 mg, 0.041 mmol) and3-((S)-2-oxo-5-(4-(piperazin-1-yl)methyl)phenyl)oxazolidin-3-yl)piperidine-2,6-dione(15.2 mg, 0.041 mmol) in DMSO (4 mL) was added KF (24 mg, 0.41 mmol).The reaction mixture was stirred at 130° C. overnight. After thereaction was cooled down to room temperature, the reaction mixture wasquenched with saturated aqueous NaHCO₃ (100 mL) and extracted with EtOAc(100 mL). The organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated. The resulting residue was purifiedby prep-TLC (DCM/MeOH=10:1) to give3-((S)-5-(4-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione(4 mg, 13% yield) as a white solid. MS (ESI) m/z: 731.0 [M+H]⁺.

Example 281:2-(2,6-Dioxopiperidin-3-yl)-5-(3-((4-(5-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione(TR-230)

Step 1. Synthesis of tert-butyl(R)-5-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of(R)-3-bromo-6-(2-(3-(fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine(1.5 g, 4.1 mmol) and tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.44 g, 4.5 mmol) in 1,4-dioxane (20 mL) and H₂O (5 mL) were addedpotassium carbonate (1.14 g, 8.2 mmol) and Pd(dppf)Cl₂ (306 mg, 0.41mmol) at room temperature. The reaction mixture was stirred at 80° C.for 4 h. The resulting black mixture was diluted with ethyl acetate (50mL), washed with saturated aqueous brine (3×50 mL). The combined organiclayers were dried over sodium sulfate, filtered, and concentrated. Theresulting residue was purified by silica gel flash chromatography(petroleum ether/ethyl acetate=1:4) to give tert-butyl(R)-5-(6-(2-(3-fluorophenl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.5 g, 78% yield) as a yellow oil. MS (ESI) m/z: 464.2 [M+H]⁺.

Step 2. Synthesis of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(1,2,5,6-tetrahydropyridin-3-yl)imidazo[1,2-b]pyridazine

To a solution of tert-butyl(R)-5-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.5 g, 3.2 mmol) in DCM (15 mL) was added TFA (3 mL) at 0° C. Thereaction mixture was stirred at room temperature for 3 h, before thesolvent was removed under vacuum. The resulting residue was washed withdiethyl ether to give(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(1,2,5,6-tetrahydropyridin-3-yl)imidazo[1,2-b]pyridazine(1.0 g, 88% yield) as a yellow solid. This product was used in the nextstep directly without further purification. MS (ESI) m/z: 364.2 [M+H]⁺.

Step 3. Synthesis of tert-butyl(R)-4-(5-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(1,2,5,6-tetrahydropyridin-3-yl)imidazo[1,2-b]pyridazine(350 mg, 0.96 mmol)and tert-butyl4-(tosyloxy)piperidine-1-carboxylate(1024 mg, 2.88 mmol) in acetonitrile (10 mL) were added potassiumcarbonate (398 mg, 3.56 mmol) and sodium iodide (144 mg, 0.96 mmol) atroom temperature. The reaction mixture was stirred at 100° C. for 2 h,before the reaction was concentrated. The resulting residue was purifiedby silica gel flash chromatography (MeOH/DCM =1:10) to give tert-butyl(R)-4-(5-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate(260 mg, 49% yield) as a yellow solid. MS (ESI) m/z: 547.8 [M+H]⁺.

Step 4. Synthesis of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(1-(piperidin-4-yl)-1,2,5,6-tetrahydropyridin-3-yl)imidazo[1,2-b]pyridazine

To a solution of tert-butyl(R)-4-(5-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate(260 mg, 0.47 mmol) in DCM (5 mL) was added TFA (1 mL) at 0° C. Thereaction mixture was stirred at room temperature for 1 h, before thesolvent was removed under vacuum. The resulting residue was washed withdiethyl ether to give(R)-6-(2-(3-fluorophenyl)pyrrolidin4-yl)-3-(1-(piperidin-4-yl)-1,2,5,6-tetrahydropyridin-3-yl)imidazo[1,2-b]pyridazine(160 mg, 75% yield) as a yellow solid. This product was used in the nextstep directly without further purification. MS (ES1) m/z: 447.8 [M+H]⁺.

Step 5. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(5-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(1-(piperidin-4-yl)-1,2,5,6-tetrahydropyridin-3-yl)imidazo[1,2-b]pyridazine(92 mg, 0.2 mmol) and(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl4-methylbenzenesulfonate(105 mg, 0.24 mmol) in acetonitrile (5 mL) were added potassiumcarbonate (75 mg, 0.6 mmol) and sodium iodide (26 mg, 0.2 mmol). Afterthe reaction mixture was stirred at 80° C. for 2 h, the reaction wasconcentrated and the resulting residue was purified by silica gelchromatography(DCM/MeOH=10:1) to give2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(5-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione(3.7 mg, 1% yield) as a yellow solid. MS (ESI) m/z: 772.1 [M+H]⁺.

Example 282:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azezetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)-amino)benzamide(TR-231)

To a solution ofN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(15 mg, 27.44 umol) and(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl4-methylbenzenesulfonate (16.38 mg, 32.93 umol) in MeCN (5 mL) was addedDIPEA (21.28 mg, 164.65 umol). After the reaction mixture was stirred at80° C. for 16 h, the solvent was removed under vacuum . The resultingresidue was purified by prep-TLC to giveN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(9.5 mg, 39% yield) as a yellow solid. MS (ESI) m/z: 873.1 [M+H]⁺.

Example 283:N-(5-(3,5-Difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(TR-232)

Step 1. Synthesis ofN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(4-methoxybenzyl)amino)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide

To a solution ofN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(80 mg, 146.36 umol) and2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(4-methoxybenzyl)amino)ethyl4-methylbenzenesulfonate (103.91 mg 175.63 mop in MeCN (5 mL) was addedDIPEA (113.49 mg, 878.14 umol). Afte the reaction mixture was stirred at90° C. for 24 h, the solvent was removed under vaccum. The resultingresidue was purified by prep-TLC to giveN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(4-methoxybenzyl)amino)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(80 mg, 57% yield) as a yellow solid. MS (ESI) m/z: 967.2 [M+H]⁺.

Step 2. Synthesis ofN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide

To a solution ofN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)(4-methoxybenzyl)amino)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide(30 mg, 31.05 umol) in DCM (2 mL) was added TFA (1 mL). After thereaction mixture was strirred at room temperature for 1 h, the reactionwas concentrated. The resulting residue was purified by prep-HPLC togiveN-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran4-yl)amino)benzamide(5 mg, 17% yield) as a yellow solid. MS (ESI) m/z: 847.1 [M+H]⁺.

Example 284:N-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(TR-233)

Step 1. Synthesis of2-chloro-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide

A mixture of 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(40 mg, 0.146 mmol) and 2-chloroacetyl chloride (82 mg, 0.732 mmol) inTHF (5 mL) was stirred at 70° C. for 1 h. After the reaction wascompleted, the reaction mixture was concentrated. The resulting residuewas triturated with petroleum ether, filtered and dried to give2-chloro-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide(55 mg, 107% yield) as a white solid. This product was used in the nextstep directly without further purification. MS (ESI) m/z: 350.4 [M+H]⁺.

Step 2. Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide

A solution of2-chloro-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide(55 mg, 0.157 mmol),(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazinehydrochloride (75 mg, 0.157 mmol) and DIEA (101 mg, 0.785 mmol) in DMF(5 mL) was stirred at 80° C. for 1 h. After the reaction was completed,the reaction solution was diluted with EtOAc (200 mL), washed with brinetwice, dried over sodium sulfate, filtered and concentrated. Theresulting residue was purified by prep-TLC (DCM/MeOH=10:1) to giveN-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide(15.5 mg, 13% yield) as a white solid. MS (ESI) m/z: 757.9 [M+H]⁺.

Example 285:2-(2,6-Dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione(TR-234)

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridine(22 mg, 4.98 umol) and(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl4-methylbenzenesulfonate (24.8 mg, 5.0 umol) in CH₃CN (4 mL) were addedNaI (15 mg, 10.0 umol) and K₂CO₃ (28 mg, 20.00 umol) at room temperatureunder N₂. The reaction mixture was stirred at 98° C. for 16 h, beforethe solvent was removed under vaccum. The resulting residue was purifiedby prep-TLC (DCM/MeOH=20:1) to give2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione(19 mg, 50% yield). MS (ESI) m/z: 769.0 [M+H]⁺.

Example 286:34(S)-5-(3-((4-(6-(6-((R)-1-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-ylmethyl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione (TR-235)

A mixture of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine(80 mg, 0.21 mmol), 2,2,2-trifluoroacetaldehyde compound with3-((S)-2-oxo-5-(3-(piperazin-1-yl)methyl)phenyl)oxazolidin-3-yl)piperidine-2,6-dione(103.23 mg, 0.21 mmol) and KF (122.01 mg, 2.1 mmol) in DMSO (1 mL) wasstirred at 130° C. for 3 h. After the reaction was cooled down to roomtemperature, the reaction was quenched with H₂O (10 mL), extracted withEtOAc. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated. The residue was purified by prep-TLC(DCM/CH₃OH=10:1) to give3-((S)-5-(3-((4-(6-(6((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione(21 mg, 14% yield) as a white solid. MS (ESI) m/z: 730.9 [M+H]⁺.

Example 287:3-(4-((2-(4-(6-(6((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazol[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-2-oxoindolin-1-yl)piperidine-2,6-dione(TR-236)

Step 1. Synthesis of 4-nitroindolin-2-one

To a solution of 4-nitro-1H-indole (5.0 g, 30.9 mmol) in CHCl₃ (200 mL)was added NCS (N-chlorosuccinimide) (2.67 g, 20 mmol) at roomtemperature. The reaction mixture was stirred at 80° C. for 48 h. Thesolvent was evaporated under reduced pressure to give a yellow solid.The solid was dissolved in AcOH (80 mL) and 85% H₃PO₄ (30 mL). Theresulting mixture was stirred at 100° C. for 3 h. After the reaction wascooled down to room temperature, the solution was acidified with 10 NNaOH to pH=6 and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with saturated brine (100 mL), dried overanhydrous sodium sulfate, filtered and evaporated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (EtOAc/petroleum ether=1:1 to 1:0) to afford the4-nitroindolin-2-one (3.5 g, 64% yield) as a yellow solid. MS (ESI) m/x:179 [M+H]⁺.

Step 2. Synthesis of 3-(4-nitro-2-oxoindolin-1-yl)piperidine-2,6-dione

To a solution of 4-nitroindolin-2-one (1.0 g, 5.6 mmol) in DMF (40 mL)was added NaH (60% in mineral oil, 247 mg, 6.2 mmol) at 0° C. Thereaction mixture was warmed to room temperature for 0.5 h, before3-bromopiperidine-2,6-dione (2.14 g, 11.2 mmol) was added. The resultingmixture was stirred at 80° C. for 1 h, before the reaction was cooleddown to room temperature. The reaction was quenched with water (50 mL)and extracted with ethyl acetate (3×20 mL). The combined organic layerswere washed with saturated brine (20 mL), dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (DCM/MeOH=30:1to 15:1) to give a mixture of 3-(4-nitro-2-oxoindolin-3-yl)piperidine-2,6-dione,3-(4-nitro-2-oxoindolin-1-yl)piperidine-2,6-dioneand 3-((4-nitro-1H-indol-2-yl)oxy) piperidine-2,6-dione (400 mg,ratio=1:1:1) as a brown solid. These products were used in the next stepdirectly without further purification. MS (ESI) m/z: 290 [M+H]⁺.

Step 3. Synthesis of 3-(4-nitro-2-oxoindolin-1-yl)piperidine-2,6-dione

A mixture of 3-(4-nitro-2-oxoindolin-3-yl)piperidine-2,6-dione,3(4-nitro-2-oxoindolin-1-yl)piperidine-2,6-dioneand 3-((4-nitro-1H-indol-2-yl)oxy)piperidine-2,6-dione (400 mg, 1:1:1)and 10% Pd/C (80 mg) in THF (10 mL) was stirred under H₂ (1 atm) at roomtemperature for 5 h. After the reaction was filtered through celite, thefiltrate was removed under reduced pressure and the residue was purifiedby prep-TLC (DCM/MeOH=10:1) to give3-(4-nitro-2-oxoindolin-1-yl)piperidine-2,6-dione (30 mg, 2% yield over2 steps) as a light yellow solid. MS (ESI) m/z: 260 [M+H]⁺.

Step 4. Synthesis of3-(4-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-2-oxoindolin-1-yl)piperidine-2,6-dione

To a solution of(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetaldehyde(57 mg, 0.12 mmol) and 3-(4-amino-2-oxoindolin-1-yl)piperidine-2,6-dione(30 mg, 0.12 mmol) in DMF (1 mL) were added TMSCl (39 mg, 0.36 mmol) andNaBH₄ (9.1 mg, 0.24 mmol) at 0° C. The reaction mixture was stirred at0° C. for 1.5 h, before it was warmed to room temperature and stirredfor 16 h. The reaction mixture was purified by prep-HPLC to give thecrude product, which was further purified by prep-TLC (DMC/MeOH=15:1) togive3-(4-((2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-2-oxoindolin-1-yl)piperidine-2,6-dione(7.7 mg, 9% yield) as a white solid. MS (ESI) m/z: 729.9 [M+H]⁺.

Example 288:2-(2,6-Dioxopiperidin-3-yl)-5-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]piperazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-yl)methyl)isoindoline-1,3-dione(TR-237)

Step 1. Synthesis of5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of2-(2,6-dioxopiperidin-3-yl)-5-methylisoindoline-1,3-dione (1 g, 3.67mmol) in CCl₄ (50 mL) were added NBS (719.10 mg, 4.04 mmol) and AIBN(azobisisobutyronitrile) (67.32 mg, 0.41mmol). After the reactionmixture was stirred at 90° C. for 16 h, the solvent was removed undervacuum. The resulting residue was purified by prep-HPLC to give5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (500mg, 40% yield) as an off-white solid. MS (ESI) m/z: 353.3 [M+H]⁺.

Step 2. Synthesis of (R)-tert-butyl3-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-y)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidine-1-carboxylate

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(300 mg, 0.68 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (139 mg,0.81 mmol) in THF (10 mL) was added titanium tetraisopropanolate (384mg, 1.35 mmol) at 0° C. Then the mixture was stirred at 60° C. for 4 h.After the reaction was cooled down to room temperature, NaBH₃CN (85 mg,1.35 mmol) was added. After the reaction mixture was stirred at roomtemperature for another 16 h, the reaction solution was poured intowater (20 mL) and extracted with ethyl acetate (3×10 mL). The combinedorganic layers were washed with saturated brine (20 mL), dried overanhydrous sodium sulfate, filtered and evaporated wider reducedpressure. The resulting residue was purified by reverse-phasechromatography to afford the desired product(R)-tert-butyl3-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidine-1-carboxylate(350 mg, 86% yield) as a yellow resin. MS (ESI) m/z: 599.8 [M+H]⁺.

Step 3. Synthesis of(R)-3-(6-(4-(azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine

To a solution of (R)-tert-butyl3-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidine-1-carboxylate(350 mg, 0.59 mmol) in DCM (5 mL) was added TFA (2 mL). The reactionmixture was stirred at 25° C. for 5 h. After the starting material wastotally consumed, the reaction was evaporated under reduced pressure togive crude(R)-3-(6-(4-(azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine(500 mg, 100% yield) as TFA salt. This product was used directly in thenext step without further purification. MS (ESI) m/z: 499.8 [M+H]⁺.

Step 4. Synthesis of2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)methyl)isoindoline-1,3-dione

To a solution of crude(R)-3-(6-(4-(azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine(50 mg, 0.06 mmol) in NMP (1 mL) was added5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (35 mg,0.1 mmol) and DIPEA (0.5 mL) at room temperature. The reaction mixturewas heated to 120° C. under microwave for 1 h. After the reaction wascooled down to room temperature, the reaction solution was poured intowater (10 mL) and extracted with ethyl acetate (3×10 mL). The combinedorganic layers were washed with saturated brine (20 mL), dried overanhydrous sodium sulfate, filtered and evaporated under reducedpressure. The residue was purified by prep-TLC (DCM/MeOH=15:1) to give2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)methyl)isoindoline-1,3-dione(13 mg, 28% yield) as a yellow solid. MS (ESI) m/z: 769.9 [M+H]⁺.

Example 289:3-(4-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(TR-238)

Step 1. Synthesis of 2-bromo-N-methyl-6-nitroaniline

To a solution of 1-bromo-2-fluoro-3-nitrobenzene (15.5 g, 70.5 mmol) inEtOH (80 mL) was added DIEA (45 g, 353 mmol) and methanaminehydrochloride (14.3 g, 211.5 mmol). After the solution was stirred at85° C. for 12 h, the reaction was cooled to room temperature,concentrated and diluted with water and ethyl acetate. The organic phasewas separated, dried over anhydrous sodium sulfate, filtered andconcentrated to give crude 2-bromo-N-methyl-6-nitroaniline (15 g, 92%yield) as a yellow solid which was used directly in the next stepwithout further purification. MS (ESI) m/z: 231.1 [M+H]⁺.

Step 2. Ssynthesis of 6-bromo-N-methylbenzene-1,2-diamine

A mixture of 2-bromo-N-methyl-6-nitroaniline (14.0 g, 60.6 mmol) in THF(40 mL) and AcOH (80 mL) was stirred at 85° C. for 2 h in the presenceof Fe (17 g, 303 mmol). The reaction mixture was filtered and thefiltrate was concentrated. The residue was purified by silica gelchromatography (petroleum ether/EtOAc=10:1) to give6-bromo-N1-methylbenzene-1,2-diamine (8.2 g, 68% yield). MS (ESI) m/z:201.2 [M+H]⁺.

Step 3. Synthesis of7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

To a solution of 6-bromo-N-methylbenzene-1,2-diamine (8.9 g, 44.5 mmol)in THF (100 mL) was added N,N″-carbonyldiimidazole (29 g, 178.2 mmol) atroom temperature under N₂. After the reaction mixture was stirred atroom temperature overnight, the solvent was removed. The residue wasdissolved in DCM/MeOH (10:1) and washed with water. The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel chromatography (DCM/MeOH=60:1) to give7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.4 g, 44%yield) as a white solid. MS (ESI) m/z: 227.2 [M+H]⁺.

Step 4. Synthesis of3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one(2.5 g, 11.0 mmol) in DMF (9 mL) was added NaH (529 mg, 60% w/wdispersed into mineral oil, 13.21 mmol) at 0° C. under nitrogenatmosphere. The reaction mixture was stirred at 0° C. for 20 min, beforea solution of 3-bromopiperidine-2, 6-dione (1.47 g, 7.71 mmol) in DMF (6mL) was added dropwise at 0° C. The resulting mixture was stirred atroom temperature overnight, before the reaction was quenched with waterand extracted with ethyl acetate (3×). The organic layers were combined,dried, filtered, and concentrated. The resulting residue was purified bysilica gel chromatography (petroleum ether/EtOAc=2:1 to DCM/MeOH=60:1)to give3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dioneas a white solid (247 mg, 7% yield). MS (ESI) m/z: 338 [M+H]⁺.

Step 5. Synthesis of3-(4-(3-hydroxyprop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(130 mg, 0.39 mmol) in DMF (3.5 mL) were added prop-2-yn-1-ol (43 mg,0.77 mmol), CuI (15 mg, 0.079 mmol), Pd(dppf)Cl₂ (29 mg, 0.04 mmol) andTEA (394 mg, 3.9 mmol). The mixture was stirred at 80° C. overnight,before the reaction was quenched with water and extracted with ethylacetate (3×). The organic layers were combined, dried, filtered, andconcentrated. The resulting residue was purified by reverse phasechromatography to give3-(4-(3-hydroxyprop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(94 mg, 78% yield) as a white solid. MS (ESI) m/z: 314.4 [M+H]⁺.

Step 6. Synthesis of3-(4-(3-chloroprop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of3-(4-(3-hydroxyprop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(30 mg, 0.096 mmol) in dry CH₂Cl₂ (2.5 mL) and anhydrous THF (1 mL) wereadded TsCl (27.6 mg, 0.14 mmol) and DMAP (35 mg, 0.29 mmol). Then thereaction mixture was stirred at room temperature for 12 h, before thereaction was quenched with water and extracted with ethyl acetate (3×).The organic layers were combined, dried, filtered, and concentrated. Theresulting residue was purified by prep-TLC (DCM/MeOH=25:1) to give3-(4-(3-chloroprop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(12 mg, 38% yield) as a white solid. MS (ESI) m/z: 332.4 [M+H]⁺.

Step 7. Synthesis of3-(4-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

A mixture of3-(4-(3-chloroprop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(12 mg, 0.036 mmol), K₂CO₃ (15 mg,0.108 mmol), NaI (8 mg, 0.054 mmol)and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazinehydrochloride (21 mg, 0.044 mmol) in CH₃CN (0.8 ml) was stirred at 90°C. for 4 h, before the reaction was quenched with water and extractedwith ethyl acetate (3×). The organic layers were combined, dried,filtered, and concentrated. The resulting residue was purified byprep-TLC DCM/MeOH=12:1) to give3-(4-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(8.6 mg, 32% yield) as a white solid. MS (ESI) m/z: 740.0 [M+H]⁺.

Example 290:3-(4-(4-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)but-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (TR-239)

TR-239 was synthesized according to the standard procedure for preparingTR-238 (5.8 mg, 16% yield). MS (ESI) m/z: 754.0 [M+H]⁺.

Example 291:3-(4-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(TR-240)

Step 1. Synthesis of3-(4-(3-hydroxypropyl)-3-methyl-2-oxo-3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

A solution of3-(4-(3-hydroxyprop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(25 mg, 0.08 mmol) in THF (3 mL) was stirred in the presence of 10% Pd/C(15 mg) under hydrogen (1 atm) for 4 h, before the reaction mixture wasfiltered. The filtrate was concentrated to give crude3-(4-(3-hydroxypropyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(30 mg, 99% yield) which was used directly in the next step withoutfurther purification. MS (ESI) m/z: 318.4 [M+H]⁺.

Step 2. Synthesis of3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propyl4-methylbenzenesulfonate

To a solution of3-(4-(3-hydroxypropyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(30 mg, 0.095 mmol) in dry CH₂Cl₂ (2 mL) and anhydrous THF (1 mL) wereadded TsCl (36 mg, 0.19 mmol) and DMAP (46 mg, 0.38 mmol). The reactionmixture was stirred at room temperature for 12 h, before the reactionwas concentrated. The resulting residue was purified by prep-TLC(DCM/MeOH=25:1) to give3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propyl4-methylbenzenesulfonate (6 mg, 13% yield) as a white solid. MS (ESI)m/z: 472.5 [M+H]⁺.

Step 3. Synthesis of3-(4-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

A mixture of3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propyl4-methylbenzenesulfonate (6 mg, 0.013 mmol), K₂CO₃ (5.3 mg, 0.038 mmol),NaI (3 mg, 0.02 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazinehydrochloride (7.5 mg, 0.016 mmol) in CH₃CN (0.8 mL) was stirred at 90°C. for 4 h, before the reaction was quenched with water and extractedwith ethyl acetate (3×). The organic layers were combined, dried,filtered, and concentrated. The resulting residue was purified byprep-TLC (DCM/MeOH=10:1) to give3-(4-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dionee (4.0 mg, 42% yield) as a white solid. MS (ESI) m/z: 744.0 [M+H]⁺.

Example 292:3-(4-(4-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)butyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(TR-241)

TR-241 was synthesized according to the standard procedure for preparingTR-240 (12 mg, 45% yield). MS (ESI) m/z: 758.1 [M+H]⁺.

Example 293.3-(3-(2-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(TR-242)

To a solution of2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl4-methylbenzenesulfonate (44.3 mg, 0.10 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine (44.2mg, 0.10 mmol) in CH₃CN (1 mL) were added sodium iodide (22.5 mg, 0.15mmol) and K₂CO₃ (41.4 mg, 0.3 mmol) at room temperature. The reactionmixture was stirred at 90° C. for 12 h. After cooled down to roomtemperature, the reaction was quenched with water and extracted withethyl acetate (3×10 mL). The combined organic layers were washed withsaturated brine (10 mL), dried over anhydrous sodium sulfate, filteredand evaporated under reduced pressure. The residue was purified byreverse-phase chromatography to afford3-(3-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (35 mg, 49% yield) as a white solid.MS (ESI) m/z: 714.9 [M+H]⁺.

Example 294:3-(3-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(TR-243)

To a solution of3-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl4-methylbenzesulfonate (45.3 mg, 0.10 mmol) and(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridine(44.2 mg, 0.10 mmol) in CH₃CN (1 mL) were added sodium iodide (22.5 mg,0.15 mmol) and K₂CO₃(41.4 mg, 0.3 mmol) at room temperature. Thereaction mixture was stirred at 90° C. for 12 h. After cooled down toroom temperature, the reaction was quenched with water and extractedwith ethyl acetate (3×10 mL). The combined organic layers were washedwith saturated brine (10 mL) dried over anhydrous sodium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby reverse-phase chromatography to afford3-(3-(3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(22 mg, 30% yield) as a white solid. MS (ESI) m/z: 729.0 [M+H]⁺.

Example 295:3(4-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(TR-244)

Step 1. Synthesis of(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol

To a solution of(R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine(200 mg, 0.42 mmol) and 2-bromoethanol (157.45 mg, 1.26 mmol) in DMSO (3mL) were added K₂CO₃ (173.89 mg, 1.26 mmol) and NaI (63.0 mg, 0.42 mmol)at room temperature. The reaction mixture was stirred at 80° C.overnight. After cooled down to room temperature, the reaction wasquenched with water (15 mL) and extracted with ethyl acetate (3×10 mL).The combined organic layers were washed with saturated brine (10 mL),dried over anhydrous sodium sulfate, filtered and evaporated underreduced pressure. The residue was purified by silica gel chromatographyto afford(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol(130 mg, 64% yield) as a brown oil. MS (ESI) m/z: 488.7 [M+H]⁺.

Step 2. Synthesis of(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl4-methylbenzenesulfonate

To a solution of(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-ol(130 mg, 0.27 mmol) in dry CH₂C₂(5 mL) were added p-toluensulfonylchloride (80.46 mg, 0.53 mmol), 4-dimethylaminopyridine (12 mg, 0.1mmol) and Et₃N (136.35 mg, 1.35 mmol) at: 0° C. Then the reactionmixture was stirred at room temperature for 24 h. The reaction wasquenched with water (5 mL) and extracted with CH₂Cl₂ (3×5 mL). Thecombined organic layers were washed with brine and dried over MgSO₁,filtered and concentrated under reduced pressure. The residue waspurified by prep-TLC to give(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl4-methylbenzenesulfonate (80 mg, 46% yield) as a white solid. MS (ESI)m/z: 642.3 [M+H]⁺.

Step 3. Synthesis of 2-(methylamino)-3-nitrophenol

To a solution of 2-fluoro-3-nitrophenol (5 g, 31.85 mmol) in EtOH (20mL) were added DIEA (26 mL, 159.25 mmol) and methenamine hydrochloride(6.45 g, 95.55 mmol). Then the reaction mixture was stirred at 90° C.for 12 h. After cooled down to room temperature, the reaction wasquenched with water (30 mL) and extracted with ethyl acetate (3×50 mL).The comined organic layers were washed with brie, dried over MgSO₄,filtered and concentrated under reduced pressure. The resulting crudeproduct was triturated with petroleum ether/EtOAc (10:1, 20 mL) to give2(methylamino)-3-nitrophenol (3.5 g, 65% yield) as a yellow solid. MS(ESI) m/z: 169.1 [M+H]⁺.

Step 4. Synthesis of2-((tert-butyldimethylsilyl)oxy)-N-methyl-6-nitroaniline

To a solution of 2-(methylamino)-3-nitrophenol (3.6 g, 21.43 mmol) andDMAP (200 mg, 1.6 mmol) in DCM (30 mL) were added triethylamine (21.6 g,214.3 mmol) and tert-butyldimethylsilyl chloride (6.4 g, 42.86 mmol).The reaction mixture was stirred at room temperature for 14 h, beforethe reaction was quenched with water (15 mL) and extracted with DCM(3×30 mL). The combined organic layers were washed with brine, driedover MgSO₄, filtered and concentrated under reduced pressure. Theresulting residue was triturated with petroleum ether/EtOAc (10:1, 22mL) to give 2-((tert-butyldimethylsilyl)oxy)-N-methyl-6-nitroaniline(3.4 g, 56% yield) as a yellow solid. MS (ESI) m/z: 283.9 [M+H]⁺.

Step 5. Synthesis of6-((tert-butyldimethylsilyl)oxy)-N1-methylbenzene-1,2-diamine

To a solution of2-((tert-butyldimethylsilyl)oxy)-N-methyl-6-nitroaniline (3.4 g, 12.06mmol) in EtOH (30 mL) was added 10% Pd/C (0.5 g). Then the mixture wasstirred under hydrogen atmosphere (1 atm) overnight. After the catalystwas filtered through celite, the filtrate was evaporated to dryness togive crude 6-((tert-butyldimethylsilyl)oxy)-N1-methylbenzene-1,2-diamine(3.0 g, 99% yield). This product was used in the next step directlywithout further purification. MS (ESI) m/z: 254.0 [M+H]⁺.

Step 6. Synthesis of7-((tert-butyldimethylsilyl)oxy)-1-methyl-1,3-dihydro-2J-benzo[d]imidazol-2-one

To a solution of6-((tert-butyldimethylsilyl)oxy)-N^(l)-methylbenzene-1,2-diamine (3.0 g,11.91 mmol) in THF (30 mL) was added N,N′-carbonyldiimidazole (5.79 g,35.73 mmol) at room temperature under N₂. The reaction mixture wasstirred at room temperature for 4 h, before the solvent was removedunder reduced pressure. The residue was recrystallized with methanol andn-hexane to give7-((tert-butyldimethylsilyl)oxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one(2.8 g, 84% yield) as a white solid. MS (ESI) m/z: 279.6 [M+H]⁺.

Step 7. Synthesis of3-(4-((tert-butyldimethylsilyl)oxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a stirred solution of7-((tert-butyldimethylsilyl)oxy)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one(600 mg, 2.16 mmol) in DMF (5 mL) was added NaH (104 mg, 60% w/wdispersed into mineral oil, 2.60 mmol) at 0° C. under nitrogenatmosphere. After the reaction mixture was stirred at 0° C. for 20 min,a solution of 3-bromopiperidine-2,6-dione (291.84 mg, 1.52 mmol) in DMF(3 mL) was added dropwise at 0° C. The resulting mixture was stirred atroom temperature for additional 3 h, before the reaction was quenchedwith AcOH (0.5 mL) and concentrated under reduced pressure to give crude3-(4-((tert-butyldimethylsilyl)oxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione.This product was used in the next step directly without furtherpurification .

Step 8. Synthesis of3-(4-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a stirred solution of3-(4-((tert-butyldimethylsilyl)oxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(crude) in DCM (10 mL) was added TFA (2 mL). The reaction mixture wasstirred at rt for 1h, before the mixture was concentrated. The residuewas purified by silica gel chromatography to give3-(4-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(70 mg, 12% yield over two steps). MS (ESI) m/z: 276.3 [M+H]⁺.

Step 9. Synthesis of3-(4-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of3-(4-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(3.05 mg, 0.012 mmol) and(R)-2-(4-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl4-methylbenzenesulfonate (5.0 mg, 0.01 mmol) in DMSO (0.5 mL) were addedK₂CO₃ (5.52 mg, 0.04 mmol) and NaI (2.25 mg, 0.015 mmol) at roomtemperature. The reaction mixture was stirred at 70° C. for 2 h. Afterthe reaction was cooled down to room temperature, the reaction wasquenched with water (10 mL) and extracted with ethyl acetate (3×10 mL).The combined organic layers were washed with saturated brine (10 mL),dried over anhydrous sodium sulfate, filtered and evaporated underreduced pressure. The resulting residue was purified by prep-HPLC toafford3-(4-(2-(4(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(1.2 mg, 16% yield) as a white solid. MS (ESI) m/z: 745.9 [M+H]⁺.

Example 296.3-(4-(3-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propoxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(TR-245)

TR 245 was synthesized according to the standard procedures forpreparing TR-244 (1.5 mg, 17% yield). MS (ESI) m/z: 759.9 [M+H]⁺.

Example 297:3-(5-(2-(4-(6-(6-((R)-2-(3-Fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(TR-246)

TR-246 was synthesized according to the standard procedures forpreparing TR-244 (5.2 mg, 19% yield). MS (ESI) m/z: 745.8 [M+H]⁺.

Certain compounds disclosed herein have the structures shown in Table 1.

TABLE 1 Cpd. Code Structure/Name CPD-001 (TR-001)

CPD-002 (TR-002)

CPD-003 (TR-003)

CPD-004 (TR-004)

CPD-005 (TR-005)

CPD-006 (TR-006)

CPD-007 (TR-007)

CPD-008 (TR-008)

CPD-009 (TR-009)

CPD-010 (TR-010)

CPD-011 (TR-011)

CPD-012 (TR-012)

CPD-013 (TR-013)

CPD-014 (TR-014)

CPD-015 (TR-015)

CPD-016 (TR-016)

CPD-017 (TR-017)

CPD-018 (TR-018)

CPD-019 (TR-019)

CPD-020 (TR-020)

CPD-021 (TR-021)

CPD-022 (TR-022)

CPD-023 (TR-023)

CPD-024 (TR-024)

CPD-025 (TR-025)

CPD-026 (TR-026)

CPD-027 (TR-027)

CPD-028 (TR-028)

CPD-029 (TR-029)

CPD-030 (TR-030)

CPD-031 (TR-031)

CPD-032 (TR-032)

CPD-033 (TR-033)

CPD-034 (TR-034)

CPD-035 (TR-035)

CPD-036 (TR-036)

CPD-037 (TR-037)

CPD-038 (TR-038)

CPD-039 (TR-039)

CPD-040 (TR-040)

CPD-041 (TR-041)

CPD-042 (TR-042)

CPD-043 (TR-043)

CPD-044 (TR-044)

CPD-045 (TR-045)

CPD-046 (TR-046)

CPD-047 (TR-047)

CPD-048 (TR-048)

CPD-049 (TR-049)

CPD-050 (TR-050)

CPD-051 (TR-051)

CPD-052 (TR-052)

CPD-053 (TR-053)

CPD-054 (TR-054)

CPD-055 (TR-055)

CPD-056 (TR-056)

CPD-057 (TR-057)

CPD-058 (TR-058)

CPD-059 (TR-059)

CPD-060 (TR-060)

CPD-061 (TR-061)

CPD-062 (TR-062)

CPD-063 (TR-063)

CPD-064 (TR-064)

CPD-065 (TR-065)

CPD-066

CPD-067

CPD-068

CPD-069

CPD-070

CPD-071

CPD-072

CPD-073

CPD-074

CPD-075

CPD-076

CPD-077

CPD-078

CPD-079

CPD-080 (TR-109)

CPD-081 (TR-107)

CPD-082

CPD-083

CPD-084

CPD-085 (TR-106)

CPD-086 (TR-105)

CPD-087 (TR-108)

CPD-088 (TR-104)

CPD-089

CPD-090 (TR-111)

CPD-091 (TR-110)

CPD-092 (TR-102)

CPD-093 (TR-059)

CPD-094

CPD-095

CPD-096

CPD-097

CPD-098

CPD-099

CPD-100

CPD-101

CPD-102

CPD-103

CPD-104

CPD-105

CPD-106 (TR-155)

CPD-107 (TR-152)

CPD-108

CPD-109

CPD-110

CPD-111 (TR-151)

CPD-112 (TR-153)

CPD-113 (TR-150)

CPD-114 (TR-149)

CPD-115 (TR-147)

CPD-116 (TR-148)

CPD-117 (TR-154)

CPD-118

CPD-119 (TR-161)

CPD-120

CPD-121 (TR-163)

CPD-122 (TR-160)

CPD-123 (TR-166)

CPD-124 (TR-144)

CPD-125 (TR-145)

CPD-126 (TR-169)

CPD-127 (TR-142)

CPD-128 (TR-138)

CPD-129 (TR-139)

CPD-130 (TR-136)

CPD-131 (TR-165)

CPD-132 (TR-167)

CPD-133 (TR-156)

CPD-134 (TR-164)

CPD-135 (TR-158)

CPD-136 (TR-157)

CPD-137 (TR-159)

CPD-138 (TR-143)

CPD-139 (TR-141)

CPD-140 (TR-146)

CPD-141 (TR-140)

CPD-142 (TR-137)

CPD-143 (TR-135)

CPD-144 (TR-134)

CPD-145 (TR-130)

CPD-146 (TR-128)

CPD-147 (TR-120)

CPD-148 (TR-119)

CPD-149 (TR-116)

CPD-150 (TR-113)

CPD-151 (TR-114)

CPD-152 (TR-122)

CPD-153 (TR-117)

CPD-154 (TR-129)

CPD-155 (TR-127)

CPD-156 (TR-124)

CPD-157 (TR-126)

CPD-158 (TR-168)

CPD-159 (TR-115)

CPD-160 (TR-123)

CPD-161 (TR-121)

CPD-162 (TR-118)

CPD-163 (TR-131)

CPD-164 (TR-132)

CPD-165 (TR-133)

CPD-166 (TR-125)

CPD-167 (TR-103)

CPD-168 (TR-162)

CPD-169 (TR-123- neg)

CPD-170 (TR-170)

CPD-171 (TR-171)

CPD-172 (TR-172)

CPD-173 (TR-173)

CPD-174 (TR-174)

CPD-175 (TR-175)

CPD-176 (TR-176)

CPD-177 (TR-177)

CPD-178 (TR-178)

CPD-179 (TR-179)

CPD-180 (TR-180)

CPD-181 (TR-181)

CPD-182 (TR-182)

CPD-183 (TR-183)

CPD-184 (TR-184)

CPD-185 (TR-185)

CPD-186 (TR-186)

CPD-187 (TR-187)

CPD-188 (TR-188)

CPD-189 (TR-189)

CPD-190 (TR-190)

CPD-191 (TR-191)

CPD-192 (TR-192)

CPD-193 (TR-193)

CPD-194 (TR-194)

CPD-195 (TR-195)

CPD-196 (TR-196)

CPD-197 (TR-197)

CPD-198 (TR-198)

CPD-199 (TR-199)

CPD-200 (TR-200)

CPD-201 (TR-201)

CPD-202 (TR-202)

CPD-203 (TR-203)

CPD-204 (TR-204)

CPD-205 (TR-205)

CPD-206 (TR-206)

CPD-207 (TR-207)

CPD-208 (TR-208)

CPD-209 (TR-209)

CPD-210 (TR-210)

CPD-211 (TR-211)

CPD-212 (TR-212)

CPD-213 (TR-213)

CPD-214 (TR-214)

CPD-215 (TR-215)

CPD-216 (TR-216)

CPD-217 (TR-217)

CPD-218 (TR-218)

CPD-219 (TR-219)

CPD-220 (TR-220)

CPD-221 (TR-221)

CPD-222 (TR-222)

CPD-223 (TR-223)

CPD-224 (TR-224)

CPD-225 (TR-225)

CPD-226 (TR-226)

CPD-227 (TR-227)

CPD-228 (TR-228)

CPD-229 (TR-229)

CPD-230 (TR-230)

CPD-231 (TR-231)

CPD-232 (TR-232)

CPD-233 (TR-233)

CPD-234 (TR-234)

CPD-235 (TR-235)

CPD-236 (TR-236)

CPD-237 (TR-237)

CPD-238 (TR-238)

CPD-239 (TR-239)

CPD-240 (TR-240)

CPD-241 (TR-241)

CPD-242 (TR-242)

CPD-243 (TR-243)

CPD-244 (TR-244)

CPD-245 (TR-245)

CPD-246 (TR-246)

Cpd. Code Chemical Name CPD-001 (2S,4R)-1-((S)-2-(6-(4-(6-(6-((R)-2-(3-(TR-001) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-002(2S,4R)-1-((S)-2-(2-(2-(2-(4-(6-(6-((R)- (TR-002)2-(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2- oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-003(2S,4R)-1-((S)-2-(tert-butyl)-20-(4-(6- (TR-003)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,20-dioxo- 6,9,12,15,18-pentaoxa-3-azaicosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamideCPD-004 (2S,4R)-1-((S)-2-(7-(4-(6-(6-((R)-2-(3- (TR-004)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperaizn-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-005(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(6- (TR-005)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,22-dioxo- 7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-006(2S,4R)-1-((S)-2-(4-(4-(6-(6-((R)-2-(3- (TR-006)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-007(2S,4R)-1-((S)-2-(3-(3-(4-(6-(6-((R)-2- (TR-007)(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3- oxopropoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-008(2S,4R)-1-((S)-2-(2-(2-(4-(6-(6-((R)-2- (TR-008)(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2- oxoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-0092-(2,6-dioxopiperidin-3-yl)-4-((7-(4-(6- (TR-009)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione CPD-0102-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2- (TR-010) (3-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione CPD-011 (2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(6-(TR-011) (6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-012(2S,4R)-1-((S)-2-(5-(4-(6-(6-((R)-2-(3- (TR-012)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridan-2-yl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-0132-(2,6-dioxopiperidin-3-yl)-4-((4-(4-(6- (TR-013)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-4-oxobutyl)amino)isoindoline-1,3-dione CPD-0142-(2,6-dioxopiperidin-3-yl)-4-((5-(4-(6- (TR-014)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione CPD-0152-(2,6-dioxopiperidin-3-yl)-4-((6-(4-(6- (TR-015)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-6-oxohexyl)amino)isoindoline-1,3-dione CPD-016(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(6- (TR-016)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-017(2S,4R)-1-((S)-2-(10-(4-(6-(6-((R)-2-(3- (TR-017)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yL)pyridin-2-yl)piperazin-1-yl)-10- oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiaozl-5- yl)benzyl)pyrrolidine-2-carboxamideCPD-018 (2S,4R)-1-((S)-2-(9-(4-(6-(6-((R)-2-(3- (TR-018)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-9-oxononamamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-019(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(6- (TR-019)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,19-dioxo- 7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-020(2S,4R)-1-((S)-2-(3-(2-(3-(4-(6-(6-((R)- (TR-020)2-(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3- oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-0212-(2,6-dioxopiperidin-3-yl)-4-((15-(4-(6- (TR-021)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)isoindoline- 1,3-dione CPD-022(2S,4R)-1-((S)-2-(11-(4-(6-(6-((R)-2-(3- (TR-022)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-11- oxoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-0232-(2,6-dioxopiperidin-3-yl)-4-((2-(4-(6- (TR-023)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione CPD-0242-(2,6-dioxopiperidin-3-yl)-4-((8-(4-(6- (TR-024)(6-((R)-2-(3-fluorophenyl)pyrroldiin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-8-oxooctyl)amino)isoindoline-1,3-dione CPD-0252-(2,6-dioxopiperidin-3-yl)-4-((18-(4-(6- (TR-025)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)isoindoline- 1,3-dione CPD-0262-(2,6-dioxopiperidin-3-yl)-4-((3-(4-(6- (TR-026)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione CPD-0272-(2,6-dioxopiperidin-3-yl)-4-((2-(3-(4- (TR-027)(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3- oxopropoxy)ethyl)amino)isoindoline-1,3-dione CPD-028 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(3- (TR-028)(4-(6-(6-((R)-2-(3- fluroophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)isoindo- line-1,3-dione CPD-029(2S,4R)-1-((S)-2-(8-(4-(6-(6-((R)-2-(3- (TR-029)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-030N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-030)yl)-4-(4-(3-(2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1- yl)-2-((tetrahydro-2H-pyrazin-4-yl)amino)benzamide CPD-031 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-031) yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)- 3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-2-((tetrahydro-2H- pyran-4-yl)amino)benzamideCPD-032 N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-032)yl)-4-(4-(3-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piper-azin-1-yl)-2-((tetrahydro-2H-pyrazin-4- yl)amino)benzamide CPD-033(2S,4R)-1-((S)-2-(8-(4-(4-((5-(3,5- (TR-033)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-034(2S,4R)-1-((S)-2-(10-(4-(4-((5-(3,5- (TR-034)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-035(2S,4R)-1-((S)-2-(11-(4-(4-((5-(3,5- (TR-035)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-11- oxoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-036(2S,4R)-1-((S)-2-(5-(4-(4-((5-(3,5- (TR-036)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-5- oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-037(2S,4R)-1-((S)-2-(9-(4-(4-((5-(3,5- (TR-037)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-9-oxononamamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-038(2S,4R)-1-((S)-2-(3-(2-(3-(4-(4-((5-(3,5- (TR-038)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-3- oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-039(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4- (TR-039)((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,16- dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-040(2S,4R)-1-((S)-2-(tert-butyl)-20-(4-(4- (TR-040)((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,20- dioxo-6,9,12,15,18-pentaoxa-3-azaicosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-041(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-(4- (TR-041)((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,19- dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-042(2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-(3,5- (TR-042)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-2- oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-043(2S,4R)-1-((S)-2-((tert-butyl)-22-(4-(4- (TR-043)((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,22- dioxo-7,10,13,16,19-pentaoxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-044(2S,4R)-1-((S)-2-(6-(4-(4-((5-(3,5- (TR-044)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-045(2S,4R)-1-((S)-2-(2-(2-(4-(4-((5-(3,5- (TR-045)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-2- oxoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-046(2S,4R)-1-((S)-2-(4-(4-(4-((5-(3,5- (TR-046)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidien-2-carboxamide CPD-047(2S,4R)-1-((S)-2-(7-(4-(4-((5-(3,5- (TR-047)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-7- oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-048(2S,4R)-1-((S)-2-(3-(3-(4-(4-((5-(3,5- (TR-048)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-3- oxopropoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-049N-(5-(3,5-difluroobenzyl)-1H_indaozl-3- (TR-049)yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-050 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-050) yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)pentanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4- yl)amino)benzamide CPD-051N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-051)yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-052 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-052) yl)-4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)octanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4- yl)amino)benzamide CPD-053N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-053)yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-054 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-054) yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)- 3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)-2-((tetrahydro-2H- pyran-4-yl)amino)benzamideCPD-055 N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-055)yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)glycyl)piperazin-1-yl)-2-((tetrahydro- 2H-pyran-4-yl)amino)benzamideCPD-056 N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-056)yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-057 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-057) yl)-4-(4-(3-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H- pyran-4-yl)amino)benzamide CPD-058(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(4- (TR-058)((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,14-dioxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamideCPD-059 N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3- (TR-059)yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3- fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamideCPD-060 N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-060)dioxoisoindolin-4-yl)amino)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-061(2S,4R)-1-((S)-2-(8-(2-(4-(4-((5-(3,5- (TR-061)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1- yl)acetamido)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-062N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-062)yl)-4-(4-(2-((2-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-2- oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-063(2S,4R)-1-((S)-2-(2-(2-(4-(4-((5-(3,5- (TR-063)difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1- yl)acetamido)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl4thiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide CPD-064N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-064)yl)-4-(4-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2- oxo-6,9,12-trioxa-3-azatetradecyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-065 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-065) yl)-4-(4-(20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2- oxo-6,9,12,15,18-pentaoxa-3-azaicosyl)piperazin-1-yl)-2-((tetrahydro- 2H-pyran-4-yl)amino)benzamideCPD-066 (2S,4R)-1-((S)-2-(9-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1- yl)acetamido)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-067(2S,4R)-1-((S)-2-(tert-butyl)-17-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,16-dioxo-6,9,12-trioxa-3,15-diazaheptadecanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-068(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-4,13-dioxo-6,9- dioxa-3,12-diazatetradecaoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamideCPD-069 (2S,4R)-1-((S)-2-(3-(2-(2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1- yl)acetamido)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-070(2S,4R)-1-((S)-2-(6-(2-(4-(6-(6-((R)-2- (3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamido)hexanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-071(2S,4R)-1-((S)-2-(4-(2-(4-(6-(6-((R)-2- (3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamido)butanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-072(2S,4R)-1-((S)-2-(5-(2-(4-(6-(6-((R)-2- (3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamido)pentanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-073(2S,4R)-1-((S)-2-(10-(2-(4-(6-(6-((R)-2- (3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamido)decanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-074(2S,4R)-1-((S)-2-(7-(2-(4-(6-(6-((R)-2- (3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamido)heptanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-075(2S,4R)-1-((S)-2-(2-(2-(4-(6-(6-((R)-2- (3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamido)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-076(2S,4R)-1-((S)-2-(2-(2-(2-(4-(6-(6-((R)- 2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamido)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-077(2S,4R)-1-((S)-20-(tert-butyl)-1-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2,18-dioxo- 6,9,12,15-tetraoxa-3,19-diazahenicosan-21-oyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-078 (2S,4R)-1-((S)-17-(tert-butyl)-1-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2,15-dioxo-6,9,12-trioxa-3,16-diazaoctadecan-18-oyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-079(2S,4R)-1-((S)-23-(tert-butyl)-1-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2,21-dioxo- 6,9,12,15,18-pentaoxa-3,22-diazatetracosan-24-oyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-080N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-109)dioxoisoindolin-4-yl)amino)propyl)-2- (4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-081N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-107)dioxoisoindolin-4-yl)amino)butyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-082(2S,4R)-1-((S)-2-(3-(2-(4-(6-(6-((R)-2- (3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamido)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-083(2S,4R)-1-((S)-2-((1-(2-(4-(6-(6-((R)-2- (3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamido)undecanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-084(2S,4R)-1-((S)-14-(tert-butyl)-1-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2,12-dioxo-6,9-dioxa-3,13-diazapentadecan-15-oyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-085N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)- (TR-106) 1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)-2-(4-(6-(6-((R)- 2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamideCPD-086 N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)- (TR-105)1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamideCPD-087 N-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-108)dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)-2-(4-(6-(6-((R)-2-(3- fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamideCPD-088 N-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-104)dioxoisoindolin-4-yl)amino)- 3,6,9,12,15-pentaoxaheptadecyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-089(2S,4R)-1-((S)-2-(8-(2-(4-(6-(6-((R)-2- (3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamido)octanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-090N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-111)dioxoisoindolin-4-yl)amino)hexyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-091N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-110)dioxoisoindolin-4-yl)amino)heptyl)-2- (4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-092N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-102)dioxoisoindolin-4-yl)amino)octyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-093N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3- (TR-059)yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3- fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamideCPD-094 (2S,4R)-1-((S)-2-(9-(2-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3- yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1- yl)acetamido)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-095(2S,4R)-1-((S)-2-(tert-butyl)-17-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,16- dioxo-6,9,12-trioxa-3,15-diazaheptadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-096(2S,4R)-1-((S)-2-(3-(2-(2-(4-(4-((5-(3,5- difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran- 4-yl)amino)phenyl)piperazin-1-yl)acetamido)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-097(2S,4R)-1-((S)-2-(4-(2-(4-(4-((5-(3,5- difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran- 4-yl)amino)phenyl)piperazin-1-yl)acetamido)butanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-098(2S,4R)-1-((S)-2-(3-(2-(4-(4-((5-(3,5- difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran- 4-yl)amino)phenyl)piperazin-1-yl)acetamido)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-099(2S,4R)-1-((S)-2-(5-(2-(4-(4-((5-(3,5- difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran- 4-yl)amino)phenyl)piperazin-1-yl)acetamido)pentanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-100(2S,4R)-1-((S)-2-(10-(2-(4-(4-((5-(3,5- difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran- 4-yl)amino)phenyl)piperazin-1-yl)acetamido)decanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-101(2S,4R)-1-((S)-2-(2-(2-(2-(4-(4-((5-(3,5- difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran- 4-yl)amino)phenyl)piperazin-1-yl)acetamido)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-102(2S,4R)-1-((S)-2-(11-(2-(4-(4-((5-(3,5- difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran- 4-yl)amino)phenyl)piperazin-1-yl)acetamido)undecanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-103(2S,4R)-1-((S)-2-(7-(2-(4-(4-((5-(3,5- difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran- 4-yl)amino)phenyl)piperazin-1-yl)acetamido)heptanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-104(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-4,13- dioxo-6,9-dioxa-3,12-diazatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-105(2S,4R)-1-((S)-2-(6-(2-(4-(4-((5-(3,5- difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran- 4-yl)amino)phenyl)piperazin-1-yl)acetamido)hexanamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-106N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-155)yl)-4-(4-(2-((4-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)amino)-2- oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-107N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-152)yl)-4-(4-(2-((3-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)amino)-2- oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-108(2S,4R)-1-((S)-23-(tert-butyl)-1-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-2,21-dioxo-6,9,12,15,18-pentaoxa-3,22-diazatetracosan-24-oyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-109(2S,4R)-1-((S)-17-(tert-butyl)-1-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2Hpyran-4-yl)amino)phenyl)piperazin-1-yl)-2,15- dioxo-6,9,12-trioxa-3,16-diazaoctadecan-18-oyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-110(2S,4R)-1-((S)-20-(tert-butyl)-1-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-2,18- dioxo-6,9,12,15-tetraoxa-3,19-diazahenicosan-21-oyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide CPD-111N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-151)yl)-4-(4-(2-((2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro- 2H-pyran-4-yl)amino)benzamideCPD-112 N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-153)yl)-4-(4-(2-((2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro- 2H-pyran-4-yl)amino)benzamideCPD-113 N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-150)yl)-4-(4-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2- oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-114 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-149) yl)-4-(4-(2-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)pentyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro- 2H-pyran-4-yl)amino)benzamideCPD-115 N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-147)yl)-4-(4-(2-((6-((2-(2,6-dioxopiepridin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)amino)-2- oxoethyl)piperazin-1-yl)-2-((tetrahdyro-2H-pyran-4-yl)amino)benzamide CPD-116N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-148)yl)-4-(4-(2-((8-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)oetyl)amino)-2- oxoethyl)piperaizn-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-117N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-154)yl)-4-(4-(2-((7-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)amino)-2- oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-118(2S,4R)-1-((S)-14-(tert-butyl)-1-(4-(4-((5-(3,5-difluorobenzyl)-1H-indazol-3-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)phenyl)piperazin-1-yl)-2,12-dioxo-6,9-dioxa-3,13-diazapentadecan- 15-yl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide CPD-119N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-161)yl)-4-(4-(2-((2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro- 2H-pyran-4-yl)amino)benzamideCPD-120 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(2-(((2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)methyl)amino)-2-oxoethyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-121 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-163) yl)-4-(4-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2- oxo-6,9,12-trioxa-3-azatetradecyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-122 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-160) yl)-4-(4-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2- oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-123 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-166) yl)-4-(4-(20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2- oxo-6,9,12,15,18-pentaoxa-3-azaicosyl)piperazin-1-yl)-2-((tetrahydro- 2H-pyran-4-yl)amino)benzamideCPD-124 N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-144)yl)-4-(4-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)-2-((tetrahydro- 2H-pyran-4-yl)amino)benzamideCPD-125 N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-145)yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5-yl)amino)propanoyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-126 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-169) yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)butanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4- yl)amino)benzamide CPD-127N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-142)yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-128 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-138) yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)hexanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4- yl)amino)benzamide CPD-129N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-139)yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5-yl)amino)heptanoyl)piperazin-1-yl)-2- ((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-130 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-136) yl)-4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)octanoyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4- yl)amino)benzamide CPD-131N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-165)yl)-4-(4-(2-((2-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)amino)-2- oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-132N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-167)yl)-4-(4-(2-((3-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)amino)-2- oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-133N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-156)yl)-4-(4-(2-((4-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)amino)-2- oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-134N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-164)yl)-4-(4-(2-((5-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)amino)-2- oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-135N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-158)yl)-4-(4-(2-((6-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)amino)-2- oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-136N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-157)yl)-4-(4-(2-((7-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptyl)amino)-2- oxoethyl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-137N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-159)yl)-4-(4-(2-((8-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)amino)-2- oxoethyl)piperazin-1-yl)-2-((tetrahdyro-2H-pyran-4-yl)amino)benzamide CPD-138N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-143)yl)-4-(4-(3-(2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoyl)piperazin-1- yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide CPD-139 N-(5-(3,5-difluorobenzyl)-1H-indazol-3-(TR-141) yl)-4-(4-(3-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)propanoyl)piper-azin-1-yl)-2-((tetrahydro-2H-pyran-4- yl)amino)benzamide CPD-140N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-146)yl)-4-(4-(3-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)-2-((tetrahydro-2H- pyran-4-yl)amino)benzamide CPD-141N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-140)yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)- 3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-2-((tetrahydro-2H- pyran-4-yl)amino)benzamideCPD-142 N-(5-(3,5-difluorobenzyl)-1H-indazol-3- (TR-137)yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)- 3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)-2-((tetrahydro-2H- pyran-4-yl)amino)benzamideCPD-143 N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)- (TR-135)1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrroldiin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-144N-(2-(2-(2-((2-(2,6-dioxopieperidin-3-yl)- (TR-134)1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamideCPD-145 N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-130)dioxoisoindolin-5-yl)amino)ethyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-146N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-128)dioxoisoindolin-5-yl)amino)hexyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-1472-(2,6-dioxopiperidin-3-yl)-5-((15-(4-(6- (TR-120)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)isoindoline- 1,3-dione CPD-1482-(2,6-dioxopiperidin-3-yl)-5-((2-(3-(4- (TR-119)(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3- oxopropoxy)ethyl)amino)isoindoline-1,3-dione CPD-149 2-(2,6-dioxopiperidin-3-yl)-5-((18-(4-(6- (TR-116)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)isoindoline- 1,3-dione CPD-1502-(2,6-dioxopiperidin-3-yl)-5-((2-(2-(3- (TR-113) (4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3- oxopropoxy)ethoxy)ethyl)amino)isoindo-line-1,3-dione CPD-151 2-(2,6-dioxopiperidin-3-yl)-5-((2-(2-(2- (TR-114)(3-(4-(6-(6-((R)-2-(3- fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino) isoindoline-1,3-dione CPD-1522-(2,6-dioxopiperidin-3-yl)-5-((6-(4-(6- (TR-122)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-6-oxohexyl)amino)isoindoline-1,3-dione CPD-1532-(2,6-dioxopiperidin-3-yl)-5-((7-(4-(6- (TR-117)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione CPD-154N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3- (TR-129)yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)ethoxy)ethyl)-2-(4-(6-(6-((R)-2-(3- fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamideCPD-155 N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-127)dioxoisoindolin-5-yl)amino)propyl)-2- (4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-156N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-124)dioxoisoindolin-5-yl)amino)butyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-157N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-126)dioxoisoindolin-5-yl)amino)heptyl)-2- (4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-1582-(2,6-dioxopiperidin-3-yl)-5-((4-(4-(6- (TR-168)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-4-oxobutyl)amino)isoindoline-1,3-dione CPD-1592-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(6- (TR-115)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione CPD-1602-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6- (TR-123)(6-((R)-2-(3-fluorophenyl)pyrroldiin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-2-oxoethyl)amino)isoindoline-1,3-dione CPD-1612-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(6- (TR-121)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione CPD-1622-(2,6-dioxopiperidin-3-yl)-5-((8-(4-(6- (TR-118)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperaizn-1-yl)-8-oxooctyl)amino)isoindoline-1,3-dione CPD-163N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-131)dioxoisoindolin-5-yl)amino)pentyl)-2- (4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-164N-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-132)dioxoisoindolin-5-yl)amino)- 3,6,9,12,15-pentaoxaheptadecyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-165N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-133)dioxoisoindolin-5-yl)amino)octyl)-2-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-166N-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-125)dioxoisoindolin-5-yl)amino)-3,6,9,12-tetraoxatetradecyl)-2-(4-(6-(6-((R)-2-(3- fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamideCPD-167 N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-103)dioxoisoindolin-4-yl)amino)pentyl)-2- (4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)acetamide CPD-168N-(5-(3,5-Difluorobenzyl)-1H-indazol- (TR-162)3-yl)-4-(4-(2-((2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)piperazin-1-yl)-2-((tetrahydro- 2H-pyran-4-yl)amino)benzamideCPD-169 5-((2-(4-(6-(6-((R)-2-(3- (TR-123- fluorophenyl)pyrrolidin-1-neg) yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione CPD-1702-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(6- (TR-170)((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)isoindoline-1,3- dione CPD-1712-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(6- (TR-171)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)propyl)amino)isoindoline-1,3-dione CPD-1722-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6- (TR-172)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)isoindoline- 1,3-dione CPD-1732-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6- (TR-173)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)isoindoline- 1,3-dione CPD-1742-(2,6-dioxopiperidin-3-yl)-5-((1-(6-(6- (TR-174)((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)amino)isoindoline- 1,3-dione CPD-1752-(2,6-dioxopiperidin-3-yl)-5-((1-(6-(6- (TR-175)((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)amino)isoindoline- 1,3-dione CPD-1762-(2,6-dioxopiperidin-3-yl)-5-((2-(2-(4- (TR-176)(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1- yl)ethoxy)ethyl)amino)isoindoline-1,3-dione CPD-177 2-(2,6-dioxopiperidin-3-yl)-5-((2-(2-(2- (TR-177)(4-(6-(6-((R)-2-(3- fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)ethoxy)ethoxy)ethyl)amino)isoindoline- 1,3-dione CPD-1782-(2,6-dioxopiperidin-3-yl)-5-(((1-(6-(6- (TR-178)((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperidin-4-yl)methyl)amino)isoindoline-1,3-dione CPD-1792-(2,6-dioxopiperidin-3-yl)-5-(((1-(6-(6- (TR-179)((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)azetidin-3-yl)methyl)amino)isoindoline-1,3-dione CPD-1802-(2,6-dioxopiperidin-3-yl)-5-((2-(1-(6- (TR-180)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperidin-4-yl)ethyl)amino)isoindoline-1,3-dione CPD-1812-(2,6-dioxopiperidin-3-yl)-5-((2-(4-(6- (TR-181)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)ethyl)amino)isoindoline-1,3-dione CPD-1822-(2,6-Dioxopiperidin-3-yl)-5-(4-(4-(6- (TR-182)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)piperidin-1- yl)isoindoline-1,3-dione CPD-1832-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6- (TR-183)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1- yl)isoindoline-1,3-dione CPD-1842-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6- (TR-184)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione CPD-185 3-(6-(3-(4-(6-(6-((R)-2-(3- (TR-185)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyrdiazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-1- oxoisoindolin-2-yl)piperidine-2,6-dioneCPD-186 3-(5-(3-(4-(6-(6-((R)-2-(3- (TR-186) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione CPD-1872-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6- (TR-187)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1- yl)isoindoline-1,3-dione CPD-1883-(5-(3-(4-(6-(6-((R)-2-(3- (TR-188) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperaizn-1-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione CPD-1893-(6-((2-(4-(6-(6-((R)-2-(3- (TR-189) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione CPD-1903-(5-((2-(4-(6-(6-((R)-2-(3- (TR-190) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione CPD-1913-(5-((2-(4-(6-(6-((R)-2-(3- (TR-191) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione CPD-1922-(2,6-Dioxopiperidin-3-yl)-5-((2-((1-(6- (TR-192)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)azetidin-3-yl)amino)ethyl)amino)isoindoline-1,3- dione CPD-1932-(2,6-Dioxopiperidin-3-yl)-5-((2-(1-(6- (TR-193)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)azetidin-3-yl)ethyl)amino)isoindoline-1,3-dione CPD-1942-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(6- (TR-194)(6-((R)-2-(3-fluorophenyl)pyrrolidni-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)-3-oxopropyl)isoindoline-1,3-dione CPD-1952-(2,6-Dioxopiperidin-3-yl)-5-((E)-3-(4- (TR-195)(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxoprop-1-en-1-yl)isoindoline-1,3-dione CPD-1963-(6-((2-(4-(6-(6-((R)-2-(3- (TR-196) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione CPD-1972-(2,6-Dioxopiperidin-3-yl)-5-((4-(6-(6- (TR-197)((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)isoindoline- 1,3-dione CPD-1982-(2,6-Dioxopiperidin-3-yl)-5-(3-((4-(6- (TR-198)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1- yl)isoindoline-1,3-dione CPD-1992-(2,6-Dioxopiperidin-3-yl)-5-((3-(2-(4- (TR-199)(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin- 1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1- yl)ethoxy)propyl)amino)isoindoline-1,3-dione CPD-200 3-(5-(2-(4-(6-(6-((R)-2-(3- (TR-200)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridaizn-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)-1- oxoisoindolin-2-yl)piperidine-2,6-dioneCPD-201 3-(6-(2-(4-(6-(6-((R)-2-(3- (TR-201) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione CPD-2023-(6-(3-(4-(6-(6-((R)-2-(3- (TR-202) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-l)-3-oxoprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione CPD-2033-(5-(3-(4-(6-(6-((R)-2-(3- (TR-203) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-3-oxoprop-1yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione CPD-2042-(2,6-dioxopiperidin-3-yl)-5-(2-(4-(6- (TR-204)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)isoindoline- 1,3-dione CPD-2053-(5-(3-((4-(6-(6-((R)-2-(3- (TR-205) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione CPD-2063-(5-((1-(6-(6-((R)-2-(3- (TR-206) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)azetidin-3-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione CPD-207 3-(5-(4-(6-(6-((R)-2-(3-(TR-207) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione CPD-2083-(5-((1-(6-(6-((R)-2-(3- (TR-208) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione CPD-209N-(2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-209)dioxoisoindolin-5-yl)-1-(6-(6-((R)-2-(3- fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)azetidine-3-carboxamideCPD-210 3-(5-(((1-(6-(6-((R)-2-(3- (TR-210) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)azetidin-3-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione CPD-2112-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6- (TR-211)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine-1-carbonyl)azetidin-1- yl)isoindoline-1,3-dione CPD-2123-(5-((1-(6-(6-((R)-2-(3- (TR-212) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione CPD-2132-((2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-213)dioxoisoindolin-5-yl)amino)-N-(1-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-y)azetidin-3-yl)acetamideCPD-214 2-(2,6-dioxo-3-piperidyl)-5-[2-[[6-[6- (TR-214)[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2- pyridyl]piperazin-1-yl]ethyl-[(4-methoxyphenyl)methyl]amino]isoindoline- 1,3-dione CPD-215N-(2-(2,6-Dioxopiperidin-3-yl)-1,3- (TR-215)dioxoisoindolin-5-yl)-1-(6-(6-((R)-2-(3- fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperidine-4-carboxamideCPD-216 3-[4-[2-[4-[6-[6-[(2R)-2-(3- (TR-216) fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]piperazin-1-yl]ethylamino]-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione CPD-217 3-[4-[3-[4-[6-[6-[(2R)-2-(3- (TR-217)fluorophenyl)pyrrolidin-1- yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]piperazin-1-yl]propylamino]-3- methyl-2-oxo-benzimidazol-2-yl]piperidine-2,6-dione CPD-218 3-(5-(((1-(6-(6-((R)-2-(3- (TR-218)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione CPD-2193-(5-((1-(6-(6-((R)-2-(3- (TR-219) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)azetidin-3-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione CPD-2203-(5-((2-(4-(6-(6-((R)-2-(3- (TR-220) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6- dione CPD-2213-[5-[3-[4-[6-[6-[(2R)-2-(3- (TR-221) fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]piperazin-1-yl]propylamino]-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione CPD-2222-(2,6-dioxo-3-piperidyl)-5-[3-[[4-[3-[6- (TR-222)[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]pyrrol-1-yl]-1-piperidyl]methyl]azetidin-1- yl]isoindoline-1,3-dione CPD-2233-((S)-5-(3-(3-(4-(6-(6-((S)-2-(3- (TR-223) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1- yl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione CPD-224 3-((S)-5-(4-(3-(4-(6-(6-((S)-2-(3-(TR-224) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1- yl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione CPD-225 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6-(TR-225) (6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1- yl)isoindoline-1,3-dioneCPD-226 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(6- (TR-226)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1- yl)isoindoline-1,3-dione CPD-2273-(3-(2-(4-(6-(6-((R)-2-(3- (TR-227) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione CPD-228 3-(3-(3-(4-(6-(6-((R)-2-(3- (TR-228)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione CPD-229 3-((S)-5-(4-((4-(6-(6-((R)-2-(3-(TR-229) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione CPD-2302-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(5- (TR-230)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3- dione CPD-231N-[5-[(3,5-difluorophenyl)methyl]-1H- (TR-231)indazol-3-yl]-4-[4-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-50yl]azetidin-3-yl]methyl]piperazin-1-yl]- 2-(tetrahydropyran-4-ylamino)benzamide CPD-232 N-[5-[(3,5-difluorophenyl)methyl]-1H- (TR-232)indazol-3-yl]-4-[4-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5- yl]amino]ethyl]piperazin-1-yl]-2-(tetrahydropyran-4-ylamino)benzamide CPD-233N-(2-(2,6-dioxopiperidin-3-yl)-1,3- (TR-233)dioxoisoindolin-5-yl)-2-(4-(6-(6-((R)-2- (3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)acetamideCPD-234 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(6- (TR-234)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1- yl)isoindoline-1,3-dione CPD-2353-((S)-5-(3-((4-(6-(6-((R)-2-(3- (TR-235) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)methyl)phenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione CPD-2363-(4-((2-(4-(6-(6-((R)-2-(3- (TR-236) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)amino)-2- oxoindolin-1-yl)piperidine-2,6-dioneCPD-237 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(6- (TR-237)(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin- 2-yl)piperazin-1-yl)azetidin-1-yl)methyl)isoindoline-1,3-dione CPD-238 3-(4-(3-(4-(6-(6-((R)-2-(3-(TR-238) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)prop-1-yn-1-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6- dione CPD-2393-(4-(4-(4-(6-(6-((R)-2-(3- (TR-239) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)but-1-yn-1-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6- dione CPD-2403-(4-(3-(4-(6-(6-((R)-2-(3- (TR-240) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol- 1-yl)piperidine-2,6-dione CPD-2413-(4-(4-(4-(6-(6-((R)-2-(3- (TR-241) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)butyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol- 1-yl)piperidine-2,6-dione CPD-2423-(3-(2-(4-(6-(6-((R)-2-(3- (TR-242) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione CPD-243 3-(3-(3-(4-(6-(6-((R)-2-(3- (TR-243)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperazin-1-yl)propyl)-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione CPD-244 3-(4-(2-(4-(6-(6-((R)-2-(3- (TR-244)fluorophenyl)pyrrolidin-1- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol- 1-yl)piperidine-2,6-dione CPD-2453-(4-(3-(4-(6-(6-((R)-2-(3- (TR-245) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)propoxy)-3-methyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6- dione CPD-246 (a)3-(5-(2-(4-(6-(6-((R)-2-(3- (TR-246) fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethoxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol- 1-yl)piperidine-2,6-dione

As used herein, in case of discrepancy between the structure andchemical name provided for a particular compound, the structure shallcontrol.

Example 298. Assessing the Effect of Selected Compounds on ReducingTPM3-TRKA Fusion Protein Levels in KM12 Colon Cancer Cells (FIG. 1A-C)

KM12 cells were treated with DMSO or indicated compounds at 100 nM for16 hours. The Western blot results showed that multiple compoundssignificantly reduced TPM3-TRKA protein levels.

Example 299. Bivalent Compounds Time-Dependently Reduced the TPM3-TRKAFusion Protein Levels in KM12 Colon Cancer Cells (FIG. 2)

KM12 cells were treated with CPD-027, CPD-053, and CPD-060 at 100 nM forindicated incubation time. The Western blot results showed that CPD-027,CPD-053, and CPD-060 rapidly reduced TPM3-TRKA protein levels.

Example 300. Bivalent Compounds Reduce TPM3-TRKA Protein Levels in KM12Subcutaneous Xenograft Tumors (FIG. 3)

Athymic nude mice bearing KM12 subcutaneous xenograft tumors at theright flank were intraperitoneally treated with 10, 20, or 50 mg/kgCPD-053, CPD-027, or CPD-060, as indicated in FIG. 3. Four hours afterdrug administration, animals were sacrificed for immunoblotting ofTPM3-TPKA in homogenized xenograft tumor chunks. The label “a” or “b”represents two different chunks of the same xenograft tumor.

Example 301. Bivalent Compounds Suppressed Viability of KM12 ColorectalCancer Cells (FIG. 4)

KM12 cells seeded in 96-well plates were treated with 500 nM entrectinibor bivalent compounds, i.e. CPD-010, CPD-053, and CPD-057 following a12-point 2-fold serial dilution for 3 days, CPD-010, CPD-053, andCPD-057 inhibited the viability of KM12 cells (FIG. 4A).

KM12 or H358 cells were treated with 1000 nM CPD-053 following an8-point 3-fold serial dilution for 3 days. CPD-053 significantlyinhibited the viability of KM12 cells but not H358 cells (FIG. 4B).

Example 302. Assessing the Effect of Selected Compounds on ReducingTPM3-TRKA Fusion Protein Levels in KM12 Colon Cancer Cells (FIG. 5A-C)

KM12 cells were treated with DMSO or indicated compounds at 0.1 nM, 1 nMor 10 nM for 16 hours. Immunoblotting data showed that all the selectedcompounds at 1 or 10 nM significantly reduced TPM3-TRKA protein levels,while at 0.1 nM the extents of degradation varied.

Example 303. Bivalent Compounds Concentration-Dependently Reduced theTPM3-TRKA Fusion Protein Levels in KM12 Colon Cancer Cells (FIG. 6A-D)

KM12 cells were treated with DMSO or indicated compounds at variousconcentrations for 16 hours. Immunoblotting results showed thatTPM3-TRKA was significantly degraded in a concentration-dependentmanner.

Example 304. Bivalent Compound Concentration-Dependently Reduced theOverexpressed TPM3-TRKA, AGBL4-TRKB and ETV6-TRKC Fusion Protein Levels(FIG. 7)

KM12 cells were infected with lentivirus that directed expression ofTPM3-TRKA, AGBL4-TRKB or ETV6-TRKC fusion. Cells were treated with DMSOor TR-123 at a range of dose for 18 hours.

Example 305. Bivalent Compound-Mediated Degradation of TRKA is Dependenton the Interaction with Cereblon (FIG. 8A-8B)

KM12 or HEL cells were treated with a dose range of compound TR-123 orTR-123-negative. The latter lost binding to cereblon (CRBN) due to achemical modification. Data showed that TR-123 reduced TRKA proteinlevels in a concentration-dependent manner while TR-123-negative hadnone or less effects on TRKA protein levels.

Example 306. Bivalent Compound Reduced TRKA Degradation is Dependent onthe Ubigutin-Proteasome System (FIG. 9A-B)

KM12 or HEL cells were treated with a single dose of compound TR-123 orcombination with MG-132, Bortezomib, MLN4924 or Pomalidomide. Datashowed that TR-123 reduced TRKA degradation is compromised by proteasomeinhibitors, MG-132 or Bortezomib, cullin E3 ligase inhibitor, MLN4924 orCRBN ligand, Pomalidomide.

Example 307. Bivalent Compounds Reduced TPM3-TRKA Protein Levels in KM12Subcutaneous Xenograft Tumors (FIG. 10A-B)

Athymic nude mice bearing KM12 subcutaneous xenograft tumors at theright flank were intraperitoneally or orally treated with bivalentcompounds at indicated close. Eight hours after drug administration,animals were sacrificed for immunoblotting of TPM3-TPKA in homogenizedxenograft tumor samples.

Example 308. The Pharmacokinetics of TR-123 (FIG. 11)

A single 20 mg/kg intraperitoneal injection of compound TR-123 wasevaluated. Plasma concentrations of TR-123 reported at each of the 6time points (30 min, 1 h, 2 h, 4 h, 8 h, and 12 h post compoundadministration) are the average values from 3 test animals. Data showeda good plasma exposure of TR123 over 12 hours.

Example 309. Bivalent Compound Showed in Vivo Anti-Tumor Activity (FIG.12A-B)

Athymic nude mice bearing KM12 subcutaneous xenograft tumors at theright flank were intraperitoneally treated with vehicle or 25 mg/kgCPD-060 once per day (qd), twice per day (bid), or once every two days(q2d). Tumor volumes were assessed every two days and expressed aslength×width×width/2. Body weights of experimental mice were alsomeasured to assess the toxicity of compounds.

Example 310. Bivalent Compounds Concentration-Dependently Reduced theTPM3-TRKA Fusion Protein Levels in KM12 Colon Cancer Cells (FIG. 13A-E)

KM12 cells were treated with DMSO or indicated compounds at variousconcentrations for 4 hours. Immunoblotting results showed that TPM3-TRKAwas significantly degraded in a concentration-dependent manner.

Example 311. The Pharmacokinetics of TR-198 in Mice (FIG. 14)

A single 2 mg/kg intravenous injection and 20 mg/kg oral gavage ofTR-198 were evaluated in mice. Plasma concentrations of TR-198 reportedat each of the 6 time points (5 min, 30 min, 2 h, 4 h, 8 h, and 12 hpost compound administration via IV, 30 min, 1 h, 2 h, 4 h, 8 h, and 12h post compound administration via p.o.) are the average values from 3test animals. Data showed around 16% oral bioavailability of TR-198 over12 hours.

Example 312. Bivalent Compound Showed in Vivo Anti-Tumor Activity (FIG.15A-B)

Athymic nude mice bearing KM12 subcutaneous xenograft tumors at theright flank were treated with vehicle, 10-20 mg/kg, TR-181 or TR-198once per day (qd), or twice per day (bid) via oral gavage. Tumor volumeswere assessed every two days and expressed as length×width×width/2. Bodyweights of experimental mice were also measured to assess the toxicityof compounds. Data showed significant in vivo anti-tumor activity ofTR-181 and TR-198.

Example 313. Bivalent Compound Exhibited Analgesic Activity inMonoiodoacetate-Induced Osteoarthritis Models of Rats and Guinea Pigs(FIG. 16A-B)

Osteoarthritis was induced in the right knee of adult male animals usingmonoiodoacetate injection. One week later, animals were treated withvehicle (Veh), 20 mg/kg TR-181, or 100 mg/kg ibuprofen (Ibu) as thepositive control. Weight distribution was determined as the percentageof weight born on the injured limb using an incapacitance meter.Response in the ibuprofen group was deter rained 2 hours after drugadministration. The other two groups was measured 6 hours followingtreatment.

Materials and Methods: General Chemistry Methods:

All chemicals and reagents were purchased from commercial suppliers andused without further purification. LCMS spectra for all compounds wereacquired using a Shimadzu LC-MS 2020 system comprising a pump (LC-20AD)with degasser (DGU-20A3), an autosampler (SIL-20AHT), a column oven(CTO-20A) (set at 40° C., unless otherwise indicated), a photo-diodearray (PDA) (SPD-M20A) detector, an evaporative light-scattering (ELSD)(Alltech 3300ELSD) detector. Chromatography was performed on a ShimadzuSunfire C18 (5 μm 50*4.6 mm) with water containing 0.1% formic acid assolvent A and acetonitrile containing 0.1% formic acid as solvent B at aflow rate of 2.0 ml/min. Flow from the column was split to a MSspectrometer. The MS detector was configured with an electrosprayionization source. Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Labsolution data system. Proton NuclearMagnetic Resonance (¹H-NMR) spectra were recorded on a Bruker AvanceIII400 spectrometer. Chemical shifts are expressed in parts per million(ppm) and reported as δ value (chemical shift δ). Coupling constants arereported in units of hertz (J value, Hz; Integration and splittingpatterns: where s=singlet, d=double, t=triplet, q=quartet, brs=broadsinglet, m=multiple). Preparative HPLC was performed on Agilent Prep1260 series with UV detector set to 254 nm or 220 nm. Samples wereinjected onto a Phenomenex Luna 75×30 mm, 5 μm, C18 column at roomtemperature. The flow rate was 40 ml/min. A linear gradient was usedwith 10% (or 50%) of MeOH (A) in H₂O (with 0.1% TFA) (B) to 100% of MeOH(A). All compounds showed >90% purity using the LCMS methods describedabove.

Plasmids

The coding sequences of human TPM3-TRKA, AGBL4-TRKB and ETV6-TRKC fusiongenes were contrcuted into pLYX-EF1α-mCherry-C1 lentiviral vector.

Cell Culture

KM12, H358, HEL and other cells were cultured at 37° C. with 5% CO₂ inRPM 1640 Medium supplemented with 10% fetal bovine serum. Cells wereauthenticated using the short tandem repeat (STR) assays. Mycoplasmatest results were negative. Stable cell lines were established bylentivirus transduction, selected and maintained in medium containing 1μg/mL puromycin (Beyotime Biotechnology).

Antibodies and Reagents

Rabbit anti-TRK antibody (92991S), phosphor-ERK antibody (4370S) andVinculin antibody (18799S) were purchased from Cell SignalingTechnology. HRP-conjugated anti-GAPDH antibody, anti-β-actin antibodyand anti-α-tubulin were produced in house. Media and other cell culturereagents were purchased from Thermo Fisher. The CellTiter-Glo Assay kitwas purchased from Promega.

Immunoblotting

Cultured cells were washed with cold PBS once and lysed in cold RIPAbuffer supplemented with protease inhibitors and phosphatase inhibitors(Beyotime Biotechnology). The solutions were then incubated at 4° C. for30 minutes with gentle agitation to fully lyse cells. For tumor tissues,tumors were cut into small pieces, milled with cold RIPA buffer using amechanical homogenizer and lysed for 1 hour at 4° C. Cell lysates werecentrifuged at 13,000 rpm for 10 minutes at 4° C. and pellets werediscarded. Total protein concentrations in the lysates were determinedby BCA assays (Beyotime Biotechnology). Cell lysates were mixed withLaemmli loading buffer to 1× and heated at 99° C. for 5 min. Proteinswere resolved on SDS-PAGE and visualized by chemiluminescence. Imageswere taken by a ChemiDoc MP Imaging system (Bio-Rad). Protein bands werequantitated using the software provided by Bio-Rad.

Cell Viability Assays

Cells were seeded at a density of 5000 cells per well in 96-well assayplates and treated with test compounds following a 12-point 2-foldserial dilution or a 8-point 3-fold dilution. Three days later, cellviability was determined using the CellTiter-Glo assay kit (Promega)according to the manufacturer's instructions. The dose-response curveswere determined and IC₅₀ values were calculated using the GraphPad Prismsoftware following a nonlinear regression (least squares fit) method.The inhibitory activities on cell viability are listed in Table 2-4below, as shown in IC₅₀ values for selected bivalent compounds.

TABLE 2 ID IC₅₀ (nM) CPD-001 >1000 CPD-002 >1000 CPD-003 >1000 CPD-004176 CPD-005 >1000 CPD-006 500 CPD-007 >1000 CPD-008 >1000 CPD-009 35CPD-010 30 CPD-011 >1000 CPD-012 >1000 CPD-013 10.2 CPD-014 7.9 CPD-01514.9 CPD-016 150 CPD-017 145 CPD-018 258 CPD-019 500 CPD-020 200 CPD-02127.4 CPD-022 100 CPD-023 14.9 CPD-024 10 CPD-025 16.7 CPD-026 82.3CPD-027 4.9 CPD-028 4.3 CPD-029 74 CPD-030 20.5 CPD-031 68.5 CPD-032 5.4CPD-033 100 CPD-034 300 CPD-035 300 CPD-036 300 CPD-037 150 CPD-038 359CPD-039 222 CPD-040 600 CPD-041 400 CPD-042 >1000 CPD-043 >1000 CPD-04473 CPD-045 >1000 CPD-046 700 CPD-047 94 CPD-048 >1000 CPD-049 73 CPD-05028 CPD-051 11 CPD-052 60 CPD-053 1.5 CPD-054 13 CPD-055 13 CPD-056 12CPD-057 6.4 CPD-058 >1000 CPD-059 6 CPD-060 6 CPD-061 >1000 CPD-062 29CPD-063 >1000 CPD-064 14.9 CPD-065 72.6

TABLE 3 ID IC₅₀ (nM) TR-102 44.4 TR-103 13.5 TR-104 8.1 TR-105 10.1TR-106 3.8 TR-107 8.4 TR-108 4.0 TR-109 3.6 TR-110 35.9 TR-111 19.7TR-113 1.3 TR-114 16.9 TR-115 0.9 TR-116 2.0 TR-117 4.3 TR-118 6.3TR-119 1.6 TR-120 10.0 TR-121 2.1 TR-122 2.7 TR-123 1.7 TR-124 2.8TR-125 2.8 TR-126 12.5 TR-127 2.7 TR-128 3.3 TR-129 4.4 TR-130 0.9TR-131 2.7 TR-132 4.4 TR-133 22.8 TR-134 5.6 TR-135 0.9 TR-136 23.6TR-137 2.5 TR-138 31.1 TR-139 27.1 TR-140 1.6 TR-141 2.6 TR-142 3.4TR-143 5.6 TR-144 2.2 TR-145 3.1 TR-146 4.2 TR-147 6.4 TR-148 23.2TR-149 4.6 TR-150 16.6 TR-151 3.1 TR-152 3.1 TR-153 6.3 TR-154 20.8TR-155 2.9 TR-156 3.3 TR-157 8.3 TR-158 6.4 TR-159 30.4 TR-160 4.8TR-161 4.7 TR-162 4.1 TR-163 6.3 TR-164 7.8 TR-165 3.5 TR-166 4.4 TR-1673.3 TR-168 2.9 TR-169 1.6 TR-170 15.1 TR-171 5.2 TR-172 2 TR-173 8.9TR-174 18.7 TR-175 40.8 TR-176 18 TR-177 1.9 TR-178 67.7 TR-179 23.4TR-180 33.8 TR-181 3.4 TR-182 16 TR-183 129 TR-184 9.3 TR-185 17.1TR-186 5.8 TR-187 18.6 TR-188 16.8 TR-189 2.5 TR-190 3.6 TR-191 5.4TR-192 103.0 TR-193 1103.0 TR-194 7.4 TR-195 23.6 TR-196 3.1 TR-197 67.1TR-198 5.5 TR-199 39.8 TR-200 101 TR-201 >500 TR-202 4.3 TR-203 3.7TR-204 10.6 Entrectinib 4.3 GNF-8625 46.7 LOXO-101 25.0

TABLE 4 ID IC₅₀ (nM) TR-205 122 TR-206 15.8 TR-207 31.3 TR-208 7TR-209 >500 TR-210 14 TR-211 2 TR-212 15.8 TR-213 22.7 TR-214 2.7TR-215 >500 TR-216 3.6 TR-217 4 TR-218 15.3 TR-219 44.9 TR-220 5.5TR-221 8.5 TR-222 >500 TR-223 11.3 TR-224 9.9 TR-225 8.8 TR-226 13.8TR-227 23.6 TR-228 56.3 TR-229 50.8 TR-230 >500 TR-231 3 TR-232 2.6TR-233 5 TR-234 284 TR-235 3.3 TR-236 99 TR-237 138 TR-238 16 TR-239 46TR-240 16 TR-241 9 TR-242 >500 TR-243 >500 TR-244 298 TR-245 >500 TR-246101

The IC₅₀ value of each compound was determined as described in FIG. 4Aand calculated using the GraphPad Prism 5.0 software.

Tumor Xenograft Studies

All animal experiments were performed under protocols approved by theInstitutional Animal Care and Use Committee (IACUC) of Cullgen. Athymicnude mice (male, 5-weeks old) received 5 million KM12 cellssubcutaneously inoculated at the right flank site. Ten days followinginoculation, tumors were approxmiately 500 mm³ in size. Tumor-bearingmice were treated intraperitoneally with vehicle or bivalent compoundsat indicated doses. Tumor sizes and body weight of mice were measuredevery 2 days. In addition, immunoblotting assays were employed to assessthe levels of TRKA fusion proteins in xenograft tumors around 500 mm³ insize following drug administration. At indicated hours after drugadministration, selected mice were sacrificed, tumors were resected.Small chunks of tumors were homogenized for immunoblotting of TPM3-TPKAand other proteins as indicated.

Mouse Pharmacokinetic (PK) Studies

Standard PK studies were conducted using male Swiss Albino mice by SaiLife Sciences. A single 20 mg/kg intraperitoneal (IP) injection ofcompound TR-123 was evaluated. Plasma concentrations of TR-123 reportedat each of the 6 time points (30 min, 1 h, 2 h, 4 h, 8 h, and 12 h postdosing) are the average values from 3 test animals. Error bars represent+SD.

Monoiodoacetate (MIA)—Induced Pain Models

Adult male Sprague Dawley rats or guinea pigs were used in theseexperiments. The baseline of hind limb weight distribution wasdetermined prior to MIA injection using an incapacitance tester (Yuyaninstruments, Shanghai, China). The weight distribution was expressed inthe following formula:

Weight on the right paw (g)÷weight on (left+right) paws×100

The next day, 2 mg MIA in 50 μl PBS solution was injected into the rightknee of experimental rats. For guinea pigs, 3 mg MIA was used. One weekfollowing MIA injection, hind limb weight distribution was measured tovalidate the symptoms. Prior to treatment, animals were randomized into2 or 3 groups (n=7), each group was treated with vehicle, 100 mg/kgibuprofen (i.m), or 20 mg/kg TR-181 (i.p.). Response to the compoundswas subsequently determined as the changes in weight distributionbetween two hind limbs.

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Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is:
 1. A bivalent compound comprising a tropomyosinreceptor kinase (TRK) ligand conjugated to a degradation tag, or apharmaceutically acceptable salt or analog thereof.
 2. The bivalentcompound of claim 1, wherein the TRK ligand is conjugated to thedegradation tag via a linker moiety.
 3. The bivalent compound of claim1, wherein the TRK ligand binds to a TRKA, TRKB, or TRKC protein.
 4. Thebivalent compound of claim 3, wherein the TRK protein comprises a TRKmutant, TRK deletion, or a TRK fusion protein.
 5. The bivalent compoundof claim 3, wherein the TRK ligand binds to the TRK protein with an IC₅₀of less than 1000 nM.
 6. The bivalent compound of claim 3, wherein thebivalent compound degrades the TRK protein in a cell.
 7. The bivalentcompound of claim 1, wherein the TRK ligand comprises a TRK kinaseinhibitor or a portion of a TRK kinase inhibitor.
 8. The bivalentcompound of claim 1, wherein the TRK ligand comprises altiratinib,sitravatinib, cabozantinib, dovitinib, entrectinib, milciclib,belizatinib, GZ389988, pegcantratinib, AZD7451, larotrectinib, TPX-0005,LOXO-195, regorafenib, DS-6051b, F17752, PLX7486, AZD-6918, ASP7962,ONO-4474, PF-06273340, or GNF-8625, or an analog thereof.
 9. Thebivalent compound of claim 1, wherein the degradation tag binds to an E3ubiquitin ligase.
 10. The bivalent compound of claim 9, wherein the E3ligase comprises a cereblon E3 ligase, a VHL E3 ligase, a MDM2 ligase, aTRIM24 ligase, a TRIM21 ligase, a KEAP1 ligase, or an IAP ligase. 11.The bivalent compound of claim 9, wherein the E3 ligase comprises acereblon E3 ligase.
 12. The bivalent compound of claim 1, wherein thedegradation tag comprises pomalidoinide, thalidomide, lenalidomide,VHL-1, adamantane, 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane,nutlin-3a, RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, or ananalog thereof.
 13. The bivalent compound of claim 1, wherein thedegradation tag comprises a hydrophobic group or a tag that leads tomisfolding of the TRK protein.
 14. The bivalent compound of claim 1,wherein administration of the bivalent compound to a cancer cell reducesviability of the cancer cell.
 15. A composition comprising the bivalentcompound of claim 1 and a pharmaceutically acceptable excipient,adjuvant, or vehicle.
 16. A method of treatment, comprisingadministering the composition of claim 15 to a subject in need thereof.17. The method of claim 16, wherein the composition is administered tothe subject orally, intravenously, parenterally, intradermally,subcutaneously, topically, or rectally.
 18. The method of claim 16,wherein the subject has a TRK-mediated disease or disorder, or a symptomthereof, comprising pain or cancer.
 19. The method of claim 18, whereinthe pain or cancer results from TRK expression, TRK overexpression, aTRK mutation, or a TRK fusion.
 20. The method of claim 18, wherein theadministration of the composition to the subject slows or preventsprogression of the pain or cancer in the subject.